RU2128644C1 - Derivatives of anthranilic acid or their pharmacologically acceptable salts, intermediate compounds used for their synthesis and drug - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to new derivatives of anthranilic acid of the general formula (I) or their pharmacologically acceptable salts where R¹, R², R³ and R⁴ are similar or distinct and mean hydrogen atom, halogen atom, optionally halogenated lower alkoxy-group, nitro-, cyano-group, pyrazolyl group, group of the formula (II) where R⁹ and R¹⁰ are similar or distinct and mean hydrogen atom, lower alkyl group and p = 0-6; group of the formula (III) where R¹³ means hydrogen atom, lower alkyl group; q = 0-2; R² can be 1,2,4- -triazolyl group; R⁵ and R⁶ are similar or distinct and mean hydrogen atom, halogen atom, cyano-group, lower alkoxy-group, or R⁵ and R⁶ together with carbon atoms to which they are bound form oxolane, 1,3-dioxolane or 1,4-dioxolane ring; W means a group -N= or -CH= ; R⁷ and R⁸ are similar or distinct and mean hydrogen atom, lower alkyl group, or R¹ and R⁷ together with carbon and nitrogen atoms, respectively, to which they are bound form piperidine or pyrrolidine ring; A means hydrogen atom, optionally halogenated lower alkyl group or a group of the formula: -X-(CH₂)_m-Z where X means -CO-, -CH₂- or S(O)₂-; Z means hydrogen, halogen atom, phenyl group that can be substituted with lower alkyl, lower alkoxy-, carboxy- or lower alkoxycarbonyl-group, pyridyl group, a group of the formula NR¹¹R¹² where R¹¹ and R¹² together with nitrogen atom to which they are bound form piperidine or pyrrolidine ring and the latter can be substituted with lower alkyl group, hydroxy-, carboxy-, lower alkoxycarbonyl-, cycloalkyl-group containing 3-8 carbon atoms that can be substituted with hydroxy-, cyano-, lower alkylcarbonylhydroxy-, carboxy- or lower alkoxycarbonyl-, piperidyl-group; m = 0-6; Y - oxygen atom; n = 0-6. Invention describes also a drug eliciting inhibiting activity with respect to cyclic GMP-phosphodiesterase based on compound of the formula (I). EFFECT: improved method of synthesis, enhanced effectiveness of drug. 5 cl, 143 ex

Description

Field of Invention
The invention relates to an anthranilic acid derivative having excellent activity as a medicine.

BACKGROUND OF THE INVENTION
Angina pectoris, which is one of the ischemic heart diseases, is known as a disease that often affects older people. Although nitrates and nitrites, calcium antagonists, β-blockers, etc. used as drugs for its treatment, these funds are still not effective in treating angina pectoris or to prevent its development in myocardial infarction. In addition, a decrease in the age of patients affected by angina pectoris and a complication of the condition of patients caused by a change in lifestyle and stress as a result of increasing difficulties in social life have recently been discovered, so the development of a new type of improved drugs is urgently needed. As for the nitrates and nitrites of the currently used drugs, it is believed that their action is associated with cyclic guanosine monophosphate (hereinafter, abbreviated as cGMP), which is one of the cyclic nucleotides known as the intracellular secondary mediator. It is well known that cGMP has relaxant activity on the smooth muscles of blood vessels and bronchi. Although the mechanism of action of this agent is not always clear, the activity of cGMP, as is usually believed, should be associated with the synthesis of cGMP accelerated by activated guanylate cyclase. However, these agents exhibit low bioavailability and are relatively short-lived; resistance to them is also reported, which becomes a clinical problem.

Description of the invention
Given these circumstances, the authors of the present invention began the development of a new type of improved drugs.

 Namely, the inventors turned their attention to the inhibitory activity against cGMP-phosphodiesterase (hereinafter, abbreviated cGMP-PDE) and intensively studied compounds possessing such activity for several years. As a result of the study, it was found that the anthranilic acid derivative described below has such activity and is effective for the treatment of various ischemic heart diseases. The present invention is made based on this finding.

 The present invention relates to an anthranilic acid derivative of the general formula (1) or pharmacologically acceptable salts thereof.

где R¹, R², R³ и R⁴ - одинаковые или различные и означают атом водорода, атом галогена, необязательно галогенированную низшую алкоксигруппу, нитро-, цианогруппу, пиразолильную группу, группу формулы

где R⁹ и R¹⁰ являются одинаковыми или различными и означают атом водорода, низшую алкильную группу и p является целым числом от 0 до 6, группу формулы

где R¹³ представляет атом водорода, низшую алкильную группу;
q является целым числом от 0 до 2;
R² может быть 1,2,4-триазолильной группой;
R⁵ и R⁶ являются одинаковыми или различными и представляют атом водорода, атом галогена, цианогруппу, низшую алкоксигруппу, или R⁵ и R⁶ вместе с атомами углерода, к которым они присоединены, образуют оксолановое кольцо, 1,3-диоксолановое или 1,4-диоксановое кольцо,
W представляет группу -N= или -CH=,
R⁷ и R⁸ - являются одинаковыми или различными и представляют атом водорода, низшую алкильную группу,
или R¹ и R⁷ вместе с атомами углерода и азота соответственно, к которым они присоединены, образуют пиперидиновое или пирролидиновое кольцо, A представляет атом водорода, необязательно галогенированную низшую алкильную группу или группу формулы:
-X-(CH₂)_m - Z,
где X представляет -CO-, -CH₂- или - S(О)₂-;
Z представляет водород, галоген, фенильную группу, которая может быть замещена низшим алкилом, низшей алкоксигруппой, карбоксигруппой или низшей алкоксикарбонильной группой, пиридильную группу, группу формулы NR¹¹R¹², где R¹¹ и R¹², вместе с атомом азота, к которому они присоединены, образуют пиперидиновое или пирролидиновое кольцо, которое может быть замещено низшей алкильной группой, оксигруппой, карбоксигруппой, низшей алкоксикарбонильной группой, циклоалкильную группу, содержащую 3-8 атомов углерода, которая может быть замещена оксигруппой, цианогруппой, низшей алкилкарбонилоксигруппой, карбоксигруппой или низшей алкоксикарбонильной группой, пиперидильной группой, m является целым числом от 0 до 6, Y представляет атом кислорода, и n является целым числом от 0 до 6.Derivatives of anthranilic acid of the general formula 1 or their pharmacologically acceptable salts

where R ¹ , R ² , R ³ and R ⁴ are the same or different and mean a hydrogen atom, a halogen atom, an optionally halogenated lower alkoxy group, a nitro, cyano group, a pyrazolyl group, a group of the formula

where R ⁹ and R ¹⁰ are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula

where R ¹³ represents a hydrogen atom, a lower alkyl group;
q is an integer from 0 to 2;
R ² may be a 1,2,4-triazolyl group;
R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form an oxolane ring, 1,3-dioxolane or 1, 4-dioxane ring,
W represents a group —N = or —CH =,
R ⁷ and R ⁸ - are the same or different and represent a hydrogen atom, a lower alkyl group,
or R ¹ and R ⁷ together with the carbon and nitrogen atoms respectively to which they are attached form a piperidine or pyrrolidine ring, A represents a hydrogen atom, an optionally halogenated lower alkyl group or a group of the formula:
-X- (CH ₂ ) _m - Z,
where X is —CO—, —CH ₂ - or —S (O) ₂ -;
Z represents hydrogen, halogen, a phenyl group which may be substituted by lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl groups, a pyridyl group, a group of formula NR ¹¹ R ¹² , where R ¹¹ and R ¹² , together with the nitrogen atom to which they attached, form a piperidine or pyrrolidine ring, which may be substituted by a lower alkyl group, an oxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group containing 3-8 carbon atoms, which may be substituted by an oxy Sing, a cyano group, a lower alkylcarbonyloxy group, a carboxy group or a lower alkoxycarbonyl group, a piperidyl group, m is an integer from 0 to 6, Y represents an oxygen atom, and n is an integer from 0 to 6.

где R¹ - R⁴ одинаковые или различные и означают атом водорода, атом галогена, цианогруппу, низшую алкоксигруппу, пиразолильную группу, R² может быть 1,2,4-триазолильной группой,
R¹⁴ представляет фенилалкил, замещенный низшей алкоксигруппой,
R¹⁵ представляет аминогруппу,
к производным антраниловой кислоты общей формулы III или их фармакологически приемлемым солям:

где R¹ - R⁴ имеют значения, указанные выше;
R⁸ означает атом водорода;
A означает атом водорода, группу формулы
-X-(CH₂)_m - Z,
где X представляет CO;
Z представляет группу формулы, -NR¹¹R¹², в которой R¹¹ и R¹² вместе с атомом азота, к которому они присоединены, образуют пиперидиновое или пирролидиновое кольцо, возможно замещенное окси-группой, карбокси-группой или низшей алкоксикарбонильной группой,
m - целое число от 0 до 6,
к производным антраниловой кислоты общей формулы IV или их фармакологически приемлемым солям:

где R¹ - R⁴ представляют атом водорода, атом галогена;
m - от 0 до 6,
Z представляет фенильную группу, замещенную низшей алкоксикарбонильной группой.The invention also relates to intermediate products for their preparation, namely, derivatives of anthranilic acid of the general formula II or their pharmacologically acceptable salts:

where R ¹ - R ^{4 are the} same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, a pyrazolyl group, R ² may be a 1,2,4-triazolyl group,
R ¹⁴ represents phenylalkyl substituted with a lower alkoxy group,
R ¹⁵ represents an amino group,
to the derivatives of anthranilic acid of the general formula III or their pharmacologically acceptable salts:

where R ¹ - R ⁴ have the meanings indicated above;
R ⁸ means a hydrogen atom;
A means a hydrogen atom, a group of the formula
-X- (CH ₂ ) _m - Z,
where X is CO;
Z represents a group of the formula —NR ¹¹ R ¹² in which R ¹¹ and R ¹² together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring, optionally substituted with an oxy group, a carboxy group or a lower alkoxycarbonyl group,
m is an integer from 0 to 6,
to derivatives of anthranilic acid of the general formula IV or their pharmacologically acceptable salts:

where R ¹ - R ⁴ represent a hydrogen atom, a halogen atom;
m - from 0 to 6,
Z represents a phenyl group substituted with a lower alkoxycarbonyl group.

 The invention also relates to a medicament exhibiting cyclic guanosine monophosphate phosphodiesterase inhibitory activity which contains an effective amount of an anthranilic acid derivative or a pharmacologically acceptable salt thereof of the general formula I and a pharmacologically acceptable carrier.

 Some of the compounds of the present invention form hydrates and there is no need to say that these hydrates fall within the scope of the present invention.

 The following will describe the main methods for producing compounds of the present invention.

 The method of obtaining 1.

(где R¹ - R⁸, A и n, каждый, определены выше).The compound represented by General formula I, where Y is an oxygen atom, can be obtained in the following way:

(where R ¹ is R ⁸ , A and n are each as defined above).

 Accordingly, this method is a method in which the anthranilic acid derivative represented by the general formula Ia can be prepared by condensing the anthranilic acid derivative represented by the general formula IIIa with an amine represented by the general formula V by a conventional method.

 Although this condensation can be carried out by a conventional method, the use of a condensing agent is preferred.

 The condensing reagent used in this method can be any conventional condensing reagent, and examples thereof include N, N'-dicyclohexylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide and 2-ethoxy-1-ethoxycarbonyl-1 2-dihydroquinoline.

 Condensation can be accelerated in the presence of N-hydroxysuccinimide or N-hydroxybenzotriazole.

 The condensation solvent may be any organic solvent inert to water and to condensation. Examples of such a solvent include ethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as benzene, toluene and xylene; dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide and pyridine.

The reaction temperature may vary from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 2.

(где R¹-R⁸, m, n и Z, каждый, определены выше).The compound represented by general formula I where A is a group of the formula —CO (CH ₂ ) _m —Z (where Z and m are each as defined above) can also be prepared by the following method:

(where R ¹ -R ⁸ , m, n and Z are each as defined above).

 Accordingly, this method is a method in which the target compound represented by general formula Ib can be prepared by reacting a compound represented by general formula VI with an anthranilic acid derivative represented by general formula VII.

 The solvent used in this reaction may be any organic solvent inert to the reaction, and examples thereof include ethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as benzene, toluene and xylene; dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide and pyridine.

The reaction temperature may vary from about -20 ^° C. to the boiling point of the solvent.

 The reaction can be accelerated by the addition of an organic base such as triethylamine, diisopropylethylamine or lutidine; or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydroxide.

 The method of obtaining 3.

(где R¹ - R⁸, m и n, каждый, определены выше, и Z' представляет защищенную карбоксильную группу).The compound represented by General formula I, where Z is a carboxyl group, can be obtained in the following way:

(where R ¹ is R ⁸ , m and n are each as defined above, and Z 'represents a protected carboxyl group).

 Accordingly, this method is a method in which the target compound represented by the general formula Ic 'can be obtained by hydrolysis of a compound represented by the general formula Ic.

 The solvent used for hydrolysis may be any organic solvent inert to hydrolysis, and examples thereof include alcohols, such as methanol and ethanol; and ethers such as tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 In addition, the presence of an inorganic base in the hydrolysis process gives the desired result, and examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and barium hydroxide.

 The method of obtaining 4.

(где R¹ - R⁸, R¹¹, R¹², n и m, каждый, определены выше; и L представляет уходящую группу, такую как атом галогена, п-толуолсульфонилоксигруппу или метансульфонилоксигруппу).The compound represented by General formula I, where Z is a group NR ¹¹ R ¹² , can also be obtained in the following way:

(where R ¹ is R ⁸ , R ¹¹ , R ¹² , n and m are each as defined above; and L represents a leaving group such as a halogen atom, a p-toluenesulfonyloxy group or a methanesulfonyloxy group).

 Accordingly, this method is a method in which the target compound represented by formula Id can be obtained by reacting a compound represented by general formula VII with an amine represented by general formula VIII.

 The solvent used in this reaction includes ethers such as ether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol and ethanol; dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N.N-dimethylformamide and dimethyl sulfoxide.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 5.

(где R¹ - R⁷, m, n и Z, каждый, определены выше).The compound represented by general formula I, where R ⁸ is hydrogen and X is represented by the formula: —CH ₂ - can be prepared by the following method:

(where R ¹ is R ⁷ , m, n and Z are each as defined above).

 Accordingly, this method is a method in which the target compound represented by general formula Ie can be obtained by reacting a compound represented by general formula IV with a compound represented by general formula V.

 The above interaction can be carried out in a solvent inert with respect to the interaction, and examples of such solvents include ethers such as ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as benzene, toluene and xylene; acetonitrile, N, N-dimethylformamide; dimethyl sulfoxide; dichloromethane; chloroform and 1,2-dichloroethane.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 In addition, the use of a catalytic amount of base in the reaction gives the desired result, and examples of the base include 4-dimethylaminopyridine and 4-pyrrolidinopyridine.

 The method of obtaining 6.

(где R¹ - R⁷ и n, каждый, определены выше).The compound represented by General formula I, where R ⁸ and A each represent a hydrogen atom, can also be obtained in the following way:

(where R ¹ is R ⁷ and n are each as defined above).

 Accordingly, this method is a method in which the target compound represented by the general formula If can be obtained by reducing the compound represented by the general formula If 'in a conventional manner.

 The reduction can be carried out by any conventional method, and examples include catalytic reduction using palladium on carbon or platinum oxide, or reduction using a metal (such as iron, tin or zinc), reduction using an acid (such as hydrochloric or acetic acid) and recovery using tin (II) chloride.

 The solvent used for the above reduction may be a solvent inert to the reduction, for example methanol or ethanol.

The reaction temperature preferably varies from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 7.

(где R¹ - R⁴, R⁸ и A, каждый, определены выше; и R¹⁴ представляет группу, выбранную из групп, определенных для R¹⁴, за исключением атомов водорода.The compound represented by General formula IIIa, which is the starting product of Production Method 1, can be prepared by the following method:

(where R ¹ is R ⁴ , R ⁸ and A are each as defined above; and R ¹⁴ represents a group selected from the groups defined for R ¹⁴ , with the exception of hydrogen atoms.

 Accordingly, a compound represented by general formula IIIa can be obtained by deprotecting a compound represented by general formula III.

When R ¹⁴ is alkyl, it is preferred that the solvent inert to the deprotection (such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane) is used in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, at a temperature of from about 0 ^o C to the boiling point of the solvent.

When R ¹⁴ is benzyl, the compound represented by general formula IIIa can be obtained by catalytic reduction using palladium on carbon or the like as a catalyst.

Furthermore, when R ¹⁴ is 4-methoxybenzyl, benzhydryl or the like, deprotection can be carried out using trifluoroacetic acid in a solvent such as dichloromethane, chloroform or 1,2-dichloroethane in the presence of anisole. In this case, it is preferable that the reaction temperature be varied from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 8.

(где Q и Q', каждый представляет атом хлора, трихлорметоксигруппу или имидазолильную группу; и R¹ - R⁴ и R¹¹ - R¹³, каждый, определены выше), (1-я стадия).A compound represented by the general formula III, wherein X is represented by the formula: —CO—; m is 0; and R ⁸ is a hydrogen atom, which is the starting product of Production Method 7, can be obtained by the following method:

(where Q and Q ', each represents a chlorine atom, trichloromethoxy group or imidazolyl group; and R ¹ - R ⁴ and R ¹¹ - R ¹³ each, as defined above), (stage 1).

 Accordingly, this step is a step in which a compound represented by general formula X is prepared by reacting a compound represented by general formula III ′ with a compound represented by general formula IX.

 An inert solvent may be used in the above reaction, and examples of the solvent include ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene and xylene.

The reaction temperature preferably varies from about 0 ^° C. to the boiling point of the solvent.

 If necessary, a base such as triethylamine or diisopropylethylamine can be used to smoothly proceed the above reaction.

 Compound X obtained in this step can be used without isolation in the next 2nd step (2nd step).

 This step is a step in which a compound represented by general formula I'b is prepared by reacting a compound X obtained in the above 1st step with a compound represented by general formula VIII.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 9.

(где R¹ - R⁴ и R¹⁴, каждый, определены выше).Among the derivatives of anthranilic acid (III ') as an initial product according to the Production Method 8, an anthranilic derivative can be prepared according to the free carboxyl group (IIa') in the following way:

(where R ¹ is R ⁴ and R ¹⁴ are each as defined above).

 Accordingly, this method is a method in which a compound represented by general formula IIa ′ can be prepared by reacting a compound represented by general formula IIa with a compound represented by general formula XII.

The reaction is preferably carried out in a solvent such as N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran or 1,4-dioxane in the presence of a base such as sodium hydrogen carbonate, sodium carbonate potassium carbonate or cesium carbonate at a temperature of from about 0 ^o C to the boiling point of the solvent.

 The method of obtaining 10.

(где Hal представляет атом галогена; L представляет уходящую группу, такую как атом галогена, п-толуолсульфонилоксигруппу или метансульфонилоксигруппу; и R¹ - R⁸, m, n и X, каждый, определены выше).The compound represented by General formula VII, which is the starting product of Production Method 4, can be prepared by the following method:

(where Hal represents a halogen atom; L represents a leaving group such as a halogen atom, a p-toluenesulfonyloxy group or a methanesulfonyloxy group; and R ¹ is R ⁸ , m, n and X are each as defined above).

 Accordingly, this method is a method in which a compound represented by general formula Id ′ can be prepared by reacting a compound represented by general formula Ia ′ with a compound represented by general formula VI ′.

 The solvent used in this reaction may be any solvent inert to the reaction, and examples of such solvents include ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile , N, N-dimethylformamide and pyridine.

The reaction temperature preferably ranges from -20 ^° C. to the boiling point of the solvent.

 In addition, the simultaneous presence of a base in the reaction gives the desired results, and examples of the base include organic bases such as triethylamine, diisopropylethylamine and lutidine; and inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and sodium hydroxide.

 The method of obtaining 11.

(где R¹ - R⁴, m, X, Hal и Z, каждый, определены выше).The compound represented by General formula IV, which is the starting product of Production Method 5, can be prepared by the following method:

(where R ¹ is R ⁴ , m, X, Hal and Z, each, as defined above).

 Accordingly, this method is a method in which the target compound represented by general formula IV can be prepared by reacting a compound represented by general formula XI with sodium hydroxide, potassium hydride or the like, and reacting the resulting product with a compound represented by general formula VI ′ .

 In the reaction, a solvent inert to the reaction can be used, and examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide and tetrahydrofuran.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 12.

(где R¹ - R⁷ и n, каждый, определены выше).The compound represented by the general formula If ', which is the starting product of Production Method 6, can be prepared by the following method:

(where R ¹ is R ⁷ and n are each as defined above).

 Accordingly, this method is a method in which a compound represented by general formula If 'can be prepared by reacting a carboxylic acid represented by general formula IIa or a reactive derivative thereof with a compound represented by general formula V by amidation.

 The reactive derivative of compound IIa includes acid halides such as acyl chloride and acyl bromide; acid azides; their active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; and their mixed acid anhydrides with p-toluenesulfonic acid and phosphoric esters.

 When free carboxylic acid is used as compound IIa, the reaction can be carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or 2-ethoxy-1-ethoxycarbonyl- 1,2-dihydroquinoline.

 When carrying out the reaction, an organic solvent inert to the reaction can be used, and examples of the solvent include ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile and N, N- dimethylformamide.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 When certain reactive compounds are used, adding a base to the reaction system gives the desired results, and examples of the base include triethylamine, diisopropylethylamine, pyridine, lutidine, sodium hydrogen carbonate, sodium carbonate and potassium carbonate.

 The method of obtaining 13.

(где R¹ - R⁴ и R¹⁴, каждый, определены выше).The compound represented by formula IIa, which is the starting product of Production Method 12, can be prepared by the following method:

(where R ¹ is R ⁴ and R ¹⁴ are each as defined above).

 Accordingly, a compound represented by general formula IIa can be obtained by deprotecting a compound represented by general formula IIa '.

The above reaction is preferably carried out in an inert solvent (such as methanol, ethanol, tetrahydrofuran or 1,4-dioxane) in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide at a temperature ranging from about 0 ^° C. to a temperature boiling solvent.

 The method of obtaining 14.

(где R¹ - R⁴ и R¹⁴, каждый, определены выше).The compound represented by General formula III ', which is the starting product according to the Production Method 8, can be obtained in the following way:

(where R ¹ is R ⁴ and R ¹⁴ are each as defined above).

 Accordingly, a compound represented by general formula III ′ can be prepared by condensing a compound represented by general formula IIIa ′ with a compound represented by general formula XII.

 Although condensation can be carried out in the usual way, the use of a condensing agent is preferred. Examples of the condensing agent include N, N'-dicyclohexylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, although any commonly known condensing agent may be used.

 The reaction can be accelerated by the addition of 4-dimethylaminopyridine or 4-pyrrolidinopyridine.

The reaction is preferably carried out in a reaction inert solvent, such as acetonitrile, dichloromethane, chloroform or N, N-dimethylformamide at a temperature ranging from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 15.

(где R¹, R³, R⁴ и R¹⁴ каждый, определены выше; М представляет атом металла; и p является целым числом от 1 до 3).A compound represented by the general formula III, wherein X is represented by the formula: —CO—; m is 0; R ² is a cyano group; and R ⁸ denotes a hydrogen atom, which is the starting product according to the Production Method 7, can be obtained in the following way:

(where R ¹ , R ³ , R ⁴ and R ^{14 are} each as defined above; M represents a metal atom; and p is an integer from 1 to 3).

 Accordingly, a compound represented by general formula XIV can be prepared by reacting a compound represented by general formula III ″ with a transition metal cyanide represented by general formula XX.

 The transition metal cyanide is preferably copper (I) cyanide.

The reaction is preferably carried out either without any solvent or in the presence of an organic solvent inert to the reaction, such as pyridine, quinoline, N, N-dimethylformamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide (HMFTA) at a temperature of from about 0 ^o C to the boiling point of the solvent.

 The method of obtaining 16.

(где R⁵, R⁶ и n, каждый, определены выше).The compound represented by General formula V, according to the Production Method 1, where R ⁷ is a hydrogen atom, can be obtained in the following way:

(where R ⁵ , R ⁶ and n are each as defined above).

 Accordingly, a compound represented by general formula V ′ can be obtained by deprotecting a compound represented by general formula XIII. Although deprotection can be carried out by acid or alkaline hydrolysis, deprotection using hydrazine is preferred.

 The solvent used in the above reaction may be any solvent inert to the reaction, and examples include methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

The reaction is preferably carried out at a temperature of from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 17.

(где R⁵,R⁶, n и L, каждый определены выше).The compound represented by general formula XIII, which is used as the starting material according to Production Method 16, can be prepared by the following method:

(where R ⁵ , R ⁶ , n and L are each as defined above).

 Accordingly, a compound represented by general formula XIII can be prepared by reacting a compound represented by general formula XIV with a phthalimide represented by general formula XV.

 When L is a hydroxy group, a compound represented by general formula XIII can be prepared by condensing a compound represented by general formula XIV with phthalimide by the Mitsunobu reaction. Although this reaction can be carried out in the usual way, it can be carried out using a derivative of phosphine, such as triphenylphosphine and tributylphosphine, and diethyl azocarboxylate or diester of azocarboxylic acid, such as diethyl azocarboxylate.

The above reaction is preferably carried out in a solvent inert to the reaction, such as tetrahydrofuran, 1,4-dioxane or acetonitrile, at a temperature of from about 0 ^° C. to the boiling point of the solvent.

 When L is a leaving group, such as a halogen atom, methanesulfonyloxy or p-toluenesulfonyloxy, the compound represented by general formula XIII can be prepared by reacting a compound of formula XIV with phthalimide or an alkali metal salt thereof. The alkali metal salt of phthalimide includes its sodium and potassium salt.

 The solvent used in the reaction may be inert to the reaction, and examples of such a solvent include acetonitrile, N, N-dimethylformamide, methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

 When phthalimide is used, the reaction can be accelerated by the addition of an inorganic base such as sodium carbonate, sodium hydrogen carbonate or potassium carbonate, or an organic base such as triethylamine, tributylamine or diazacycloundecene.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 18.

(где R² - R⁶, n и L, каждый, определены выше).The compound represented by General formula I, where Y is an oxygen atom, and R ¹ and R ^{7 are} joined together to form a ring, can be obtained in the following way:

(where R ² is R ⁶ , n and L are each as defined above).

 Accordingly, a compound represented by general formula Ig can be prepared by reacting a compound represented by general formula Ig 'with a compound represented by general formula XVI.

 Preferably, the reaction is carried out in the presence of a base such as sodium hydride, potassium hydride or potassium tert-butoxide.

The reaction is preferably carried out in a solvent inert to the reaction, such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, at a temperature of from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 19.

(где R² - R⁴, R¹⁴ и L, каждый, определены выше; и q представляет целое число от 1 до 6). (1-я стадия)
Соответственно, соединение, представленное общей формулой XVIII, получают взаимодействием соединения, представленного общей формулой XVII, с аммиаком.The compound represented by the general formula Ig ', which is the starting product of Production Method 18, can be prepared by the following method:

(where R ² is R ⁴ , R ¹⁴ and L are each as defined above; and q represents an integer from 1 to 6). (1st stage)
Accordingly, a compound represented by general formula XVIII is prepared by reacting a compound represented by general formula XVII with ammonia.

 When carrying out the reaction, a solvent inert to the reaction can be used, and examples of the solvent include methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent. (2nd stage)
Accordingly, a compound represented by general formula Ig ′ is prepared by reducing a compound represented by general formula XVIII in a conventional manner.

 The reduction can be carried out in the usual way, and examples of the method include catalytic reduction using palladium on carbon or platinum oxide; reduction with a metal, such as iron, tin or zinc, and an acid, such as hydrochloric acid or acetic acid; and reduction with tin (II) chloride.

 The solvent used in the reduction may be a solvent inert to the reaction, for example methanol or ethanol.

The reaction is carried out at a temperature of from 0 ^o C to the boiling point of the solvent.

 The method of obtaining 20.

(где R² - R⁴, R¹⁴, L и q, каждый, определены выше). (1-я стадия)
Соответственно, соединение, представленное общей формулой XVIII, получают взаимодействием соединения, представленного общей формулой XVII, с цианидом металла.The compound represented by the general formula Ig ', which is the starting product of Production Method 18, can also be prepared by the following method:

(where R ² is R ⁴ , R ¹⁴ , L and q are each as defined above). (1st stage)
Accordingly, a compound represented by general formula XVIII is prepared by reacting a compound represented by general formula XVII with metal cyanide.

 In carrying out the above reaction, a solvent inert to the reaction can be used, and examples of such solvents include water, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent. (2nd stage)
Accordingly, a compound represented by general formula Ig ′ is prepared by reducing a compound represented by general formula XVIII in a conventional manner.

 This reduction can be carried out in the usual way, and examples include catalytic reduction using palladium on carbon or platinum oxide; reduction with a metal, such as iron, tin or zinc, and an acid, such as hydrochloric acid or acetic acid; and reduction with tin (II) chloride.

 The solvent used in the reduction may be a solvent inert to the reduction, for example, methanol or ethanol.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

 The method of obtaining 21.

(где R³, R⁴ и X, каждый, определены выше).The compound represented by the General formula Ig ', where R ² is a halogen atom, which is the starting product of Production Method 18, can be obtained in the following way:

(where R ³ , R ⁴ and X are each as defined above).

 Accordingly, the compound represented by general formula Ig ′ can be prepared by halogenating the compound represented by general formula XIX in a conventional manner.

 This halogenation can be carried out in the usual way, and examples of the method include methods using chlorine, bromine, tetra-n-butylammonium tribromide and benzyltrimethylammonium tribromide, respectively.

 The solvent used in the halogenation may be a solvent inert to the halogenation, for example dichloromethane, chloroform or acetic acid.

The reaction temperature preferably ranges from about 0 ^° C. to the boiling point of the solvent.

(где R¹, R², R³ и R⁴, каждый, определены выше; R¹⁴ представляет атом водорода, необязательно галогенированную низшую алкильную группу или необязательно замещенную арилалкильнцю группу; и R¹⁵ представляет нитрогруппу или аминогруппу).The present invention also relates to the following compounds: compounds represented by general formula II and their pharmacologically acceptable salts:
general formula II

(where R ¹ , R ² , R ³ and R ⁴ are each as defined above; R ¹⁴ represents a hydrogen atom, an optionally halogenated lower alkyl group or an optionally substituted arylalkyl group; and R ¹⁵ represents a nitro group or an amino group).

(где R¹, R², R³, R⁴, R⁸, R¹⁴ и A, каждый, определены выше);
и соединения, представленные общей формулой IV, и их фармакологически приемлемые соли:
общая формула IV

(где R¹, R², R³, R⁴, m и Z, каждый, определены выше; и X² представляет группу -CH₂-).The compounds represented by general formula III and their pharmacologically acceptable salts:
general formula III

(where R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ¹⁴ and A are each as defined above);
and compounds represented by general formula IV, and pharmacologically acceptable salts thereof:
general formula IV

(where R ¹ , R ² , R ³ , R ⁴ , m and Z are each as defined above; and X ² represents the group —CH ₂ -).

 These compounds II, III and IV are used as intermediates for the preparation of compounds I.

 The following describes a pharmacological experimental example to demonstrate the usefulness of the compounds of the present invention.

Pharmacological experimental example
Enzymatic inhibitory activity using cGMP-PDE obtained from porcine aorta
1. The methodology of experience
The enzymatic activity of cGMP-PDE obtained from porcine aorta was determined by the method of Thompson et al. This determination was carried out in the presence of 1 mM EGTA using 1 μM cGMP as a substrate. Each compound of the present invention was dissolved in DMSO and added to the reaction system to determine its inhibitory activity. The final concentration of DMSO in the reaction system is set to 4% or lower.

cGMP-PDE was prepared as follows:
The pig’s aorta was cut into small pieces, 10-fold volume of buffer A was added (20 mM Tris / HCl, 2 mM magnesium acetate, 1 mM dithiothreitol, 5 mM EDTA, 1400 TIU / l aprotinin, 10 mg / l leupeptin, 1 mM benzamidine, 0.2 mM PMSF, pH 7.5). The resulting mixture was homogenized and centrifuged at 100,000 rpm. The resulting supernatant (supernatant) was placed on a DEAE-Toyopearl 650S column (product of Tosoh, Tokyo, Japan), followed by washing the column with buffer B (50 mM Tris / HCl, 0.1 mM EGTA, 2 mM magnesium acetate, 1 mM Dithiothreitol, 0.2 mM PMSF, pH 7.5). The resulting column was subjected to gradient elution with 0.05-0.4 M sodium chloride to obtain CaM-independent fractions of cGMP-PDE.

2. The results of the experiment
The inhibitory activity of cGMP-PDE compounds of the present invention, thus defined, is shown in Table 1, where a lower IC ₅₀ (IC ₅₀ ) reflects a more significant effect.

 From the results of the Pharmacological Experimental Example, it can be understood that the compound of the present invention has inhibitory activity against PDE, in particular cGMP-PDE. In other words, it can be understood that the compound of the present invention has the effect of increasing the in vivo concentration of cGMP due to the inhibitory activity against cGMP-PDE. Accordingly, the anthranilic acid derivatives of the present invention are effective in the prevention and treatment of diseases for which the cGMP-PDE inhibitory effect is effective. Examples of such diseases include ischemic heart diseases such as angina pectoris, myocardial infarction, chronic and acute heart failure; pulmonary hypertension, with or without pulmonary heart disease; hypertension due to various reasons; peripheral circulatory failure; cerebrovascular insufficiency; brain dysfunction; and allergic diseases such as bronchial asthma, atonic dermatitis and allergic rhinitis.

 In addition, the compounds of the present invention are less toxic and safer, thus being useful in this sense.

 The present invention relates to a prophylactic and therapeutic agent for the treatment of diseases for which phosphodiesterase inhibition is effective, the agents comprising anthranilic acid derivatives or their pharmacologically acceptable salts described above as active components; and prophylactic and therapeutic agents for treating diseases for which cyclic GMP inhibition is effective, wherein the agent contains an anthranilic acid derivative or a pharmacologically acceptable salt thereof, as described above, as an active ingredient.

 The compound of the present invention is particularly effective against ischemic heart disease, angina pectoris, hypertension, pulmonary hypertension, heart failure and asthma.

 In addition, the present invention relates to a medicament comprising a pharmacologically effective amount of an anthranilic acid derivative or a pharmacologically acceptable salt thereof described above, and a pharmacologically acceptable carrier; and to a method for the prevention and treatment of diseases, which comprises administering a pharmacologically acceptable amount of an anthranilic acid derivative or a pharmacologically acceptable salt thereof described above to inhibit phosphodiesterase.

 The compound of the present invention is administered as a medicament orally or parenterally. Its dose varies depending on the degree of the disease; age, gender, weight, and drug sensitivity; drug regimens; timing of dosing; interval between receptions; type of drug; medication administered at the same time; the type of active component, etc., but is not limited to this.

 When administered orally, the daily dose for an adult is usually about 0.1-1000 mg, preferably about 5-500 mg, which can be administered from one to three servings per day.

 When administered as an injection, the daily dose is usually from about 1 μg / kg to 3000 μg / kg, preferably about 3-1000 μg / kg.

 A solid preparation for oral administration according to the present invention is prepared by adding an excipient and, if necessary, a binder, disintegrant, lubricant, dye and / or additive to the active ingredient and molding the resulting mixture into tablets, coated tablets, granules, powders or capsules.

 Examples of filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; examples of a binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, calcium citrate, dextrin and pectin; examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils; examples of a colorant include colorants approved as pharmaceutical additives; and examples of additives include cocoa powder, menthol, aromatic powder, menthol oil, borneol and cinnamon powder. Of course, tablets and granules may be suitably coated with sugar, gelatin or the like, if necessary.

 When an injectable preparation is prepared, according to the present invention, a pH regulator, a buffer, a suspending agent, a solubilizing agent, a stabilizer, an isotonic agent and / or a preservative can be added to the active ingredient, if necessary, and the mixture is prepared for intravenous, subcutaneous or intramuscular administration in the usual way. In addition, the injectable preparation can be freeze-dried, if necessary.

 Examples of the suspending agent include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolaurate.

 Examples of the solubilizing agent include polyoxyethylene, solidifying castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol and castor oil fatty acid ethyl ester.

 Next, for a clearer understanding of the present invention, examples will be described, although they precede the Preparative examples as synthesis examples, which give the starting compounds necessary for the preparation of the compounds of the present invention.

Анизол (4,7 мл) добавляют к 4,09 г этил-1-[[4-хлор-2-[(4- метоксибензилохси)карбонил] фенил] карбамоил]пиперидин-4-карбоксилата, затем по каплям добавляют 6,6 мл трифторуксусной кислоты. Полученную смесь перемешивают при комнатной температуре один час и концентрируют и добавляют эфир. Образующуюся смесь экстрагируют насыщенным водным раствором гидрокарбоната натрия. pH водного раствора устанавливают 2 с помощью концентрированной соляной кислоты для осаждения кристаллов. Кристаллы выделяют фильтрованием и промывают водой с получением 2,09 г указанного в заголовке соединения в виде белого порошка (выход: 69%).Preparative example 1
1 - [(2-Carboxy-4-chlorophenyl) carbamoyl] piperidine-4-carboxylic acid

Anisole (4.7 ml) was added to 4.09 g of ethyl 1 - [[4-chloro-2 - [(4-methoxybenzyloxy) carbonyl] phenyl] carbamoyl] piperidine-4-carboxylate, then 6.6 was added dropwise. ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for one hour and concentrated and ether was added. The resulting mixture was extracted with saturated aqueous sodium bicarbonate. The pH of the aqueous solution was adjusted to 2 with concentrated hydrochloric acid to precipitate crystals. The crystals were isolated by filtration and washed with water to give 2.09 g of the title compound as a white powder (yield: 69%).

Mp 159-160 ^o C (decomp.)
(white needles from water ethanol).

NMR (400 MHz, δ, CDCl ₃ ):
1.27 (t, J-7.1 Hz, 3H), 1.78 (m, 2H), 2.02 (m, 2H), 2.58 (m, 1H), 3.10 (m, 2H), 4.11 (m, 2H), 4.18 (q , J = 7.1 Hz, 2H), 7.47 (dd, J = 2.7, 9.2 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 9.2 Hz, 1H), 10.70 (s , 1H).

К 4-метоксибензил-2-амино-5-хлорбензоату (20.74 г), растворенному в 180 мл тетрагидрофурана, добавляют 12.69 г 1,1'-карбонилдиимидазола. Полученную смесь кипятят с обратным холодильником 43 ч и оставляют охлаждаться, затем добавляют 12.06 мл этилизонипекотата. Полученную смесь выдерживают при комнатной температуре один час и концентрируют, добавляют воду и экстрагируют этилацетатом. Органическую фазу промывают 1H соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором обычной соли, последовательно, сушат над безводным сульфатом магния и отгоняют растворитель. Hерастворимое в бензоле вещество отфильтровывают, а фильтрат очищают колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3:1)) и получают 11.07 г указанного в заголовке соединения в виде желтого масла с выходом 33%.Preparative example 2
Ethyl 1 - [[4-chloro-2- (4-methoxybenzyloxy) carbonylphenyl] carbamoyl] - piperidine-4-carboxylate

To 4-methoxybenzyl-2-amino-5-chlorobenzoate (20.74 g) dissolved in 180 ml of tetrahydrofuran was added 12.69 g of 1,1'-carbonyldiimidazole. The resulting mixture was refluxed for 43 hours and allowed to cool, then 12.06 ml of ethyl isonipecotate was added. The resulting mixture was kept at room temperature for one hour and concentrated, water was added and extracted with ethyl acetate. The organic phase is washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous ordinary salt, successively, dried over anhydrous magnesium sulfate and the solvent is distilled off. The benzene insoluble material was filtered off and the filtrate was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)) to obtain 11.07 g of the title compound as a yellow oil in 33% yield.

NMR (400 MHz, δ, CDCl ₃ ):
1.27 (t, J = 7.1 Hz, 3H), 1.76 (m, 2H), 2.01 (m, 2H), 2.54 (m, 1H), 3.07 (m, 2H), 3.83 (s, 3H), 4.12 (m , 2H), 4.32 (q, 7.1 Hz, 2H), 5.28 (s, 2H), 6.91-6.96 (m, 2H), 7.36-7.40 (m, 2H), 7.43 (dd, J - 2.6, 9.2 Hz, 1H), 7.95 (d, J = 2.6 Hz), 8.66 (d, J = 9.2 Hz), 10.68 (s, 1H).

2-Амино-5-хлорбензойную кислоту (15.00 г), метоксибензилхлорид (13.1 мл) и карбонат калия (13.3 г) добавляют к N,N-диметилформамиду (175 мл). Полученную смесь перемешивают при комнатной температуре 43 ч, затем к смеси добавляют ледяную воду. Полученную смесь экстрагируют этилацетатом. Органическую фазу промывают водой и насыщенным раствором хлорида натрия, сушат над безводным сульфатом магния и растворитель отгоняют. Остаток очищают колоночной хроматографией на силикагеле (растворитель н-гексан/этилацетат (5:1)) и получают 20.97 г указанного в заголовке соединения в виде бледно-желтого масла с выходом 82%.Preparative example 3
4-methoxybenzyl-2-amino-5-chlorobenzoate

2-amino-5-chlorobenzoic acid (15.00 g), methoxybenzyl chloride (13.1 ml) and potassium carbonate (13.3 g) are added to N, N-dimethylformamide (175 ml). The resulting mixture was stirred at room temperature for 43 hours, then ice water was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with water and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate (5: 1)) to obtain 20.97 g of the title compound as a pale yellow oil in 82% yield.

NMR (400 MHz, δ, CDCl ₃ ):
3.82 (s, 3H), 5.24 (s, 2H), 5.74 (w, 2H), 6.59 (d, J = 8.8 Hz, 1H), 6.89-6.94 (m, 2H), 7.18 (dd, J = 2.6, 8.8 Hz, 1H), 7.34-7.39 (m, 2H), 7.82 (d, J = 2.6 Hz, 1H).

Метил-5-диметиламинометил-2-нитробензоат (12.92 г) и дигидрат хлорида олова(II) (60.39 г) добавляют к 110 мл этанола. Полученную смесь перемешивают при 70^oC в течение одного часа, затем добавляют ледяную воду. Полученную смесь подщелачивают карбонатом натрия и экстрагируют этилацетатом. Органическую фазу сушат безводным сульфатом магния и растворитель отгоняют. Остаток очищают колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол (от 30: 1 до 10:1)) и получают 10.93 г указанного в заголовке соединения в виде бледно-желтой жидкости с выходом 97%.Preparative example 4
Matyl-2-amido-5-dimethylaminomethylbenzoate

Methyl 5-dimethylaminomethyl-2-nitrobenzoate (12.92 g) and tin (II) chloride dihydrate (60.39 g) are added to 110 ml of ethanol. The resulting mixture was stirred at 70 ^° C. for one hour, then ice water was added. The resulting mixture was made alkaline with sodium carbonate and extracted with ethyl acetate. The organic phase was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1 to 10: 1)) to obtain 10.93 g of the title compound as a pale yellow liquid in 97% yield.

NMR (400 MHz, δ, CDCl ₃ ):
2.20 (s, 6H), 3.29 (s, 2H), 3.85 (s, 3H), 5.68 (w, 2H), 6.63 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 2.2, 8.4 Hz , 1H), 7.74 (d, J = 2.2 Hz, 1H).

К метил-5-метил-2-нитробензоату (8.06 г), растворенному в 140 мл четыреххлористого углерода, добавляют 7.72 г N-бромсукцинимида и 0.50 г бензоилпероксида. Полученную смесь кипятят с обратным холодильником 5 ч и отфильтровывают нерастворимый материал. Фильтрат концентрируют до получения желтого масла. Это масло растворяют в 80 мл ацетонитрила, добавляют 4.04 г хлоргидрата диметиламина и 6.86 г карбоната калия. Полученную смесь перемешивают при комнатной температуре 5 ч и концентрируют, затем добавляют воду. Полученную смесь экстрагируют этилацетатом. Органическую фазу сушат безводным сульфатом магния и растворитель отгоняют. Остаток очищают колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол (30:1)) и получают 3.17 г целевого соединения в виде желтого масла с выходом 32%.Preparative example 5
Methyl 5-dimethylaminomethyl-2-nitrobenzoate

To methyl 5-methyl-2-nitrobenzoate (8.06 g) dissolved in 140 ml of carbon tetrachloride, 7.72 g of N-bromosuccinimide and 0.50 g of benzoyl peroxide are added. The resulting mixture was refluxed for 5 hours and insoluble material was filtered off. The filtrate was concentrated to a yellow oil. This oil is dissolved in 80 ml of acetonitrile, 4.04 g of dimethylamine hydrochloride and 6.86 g of potassium carbonate are added. The resulting mixture was stirred at room temperature for 5 hours and concentrated, then water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)) to obtain 3.17 g of the target compound as a yellow oil in 32% yield.

NMR (400 MHz, δ, CDCl ₃ ):
2.26 (s, 6H), 3.51 (s, 2H), 3.93 (s, H) 7.59 (dd, J = 1.8, 8.4 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H).

1.11 г 60% гидрида натрия (суспендированного в минеральном масле) суспендируют в 80 мл N, N-диметилацетамида и по частям добавляют 5.00 г 6-хлор-1,2-дигидро-4H-3,1-бензоксазин-2,4-диона. Полученную смесь перемешивают при комнатной температуре в течение одного часа и добавляют 4.81 мл этил-5-бромвалерата. Полученную смесь перемешивают при 50^oC 24 ч, выливают в 200 мл смеси 1H соляной кислоты и льда и экстрагируют этилацетатом. Органическую фазу промывают водой и насыщенным водным раствором соли, сушат безводным сульфатом магния и растворитель отгоняют. К полученному твердому остатку либо добавляют эфир. Полученную смесь фильтруют и получают 4.89 г целевого соединения в виде бледно-желтого порошка, выход 60%.Preparative example 6
6-Chloro-1- [4- (ethoxycarbonyl) butyl] -1,2-dihydro-4H-1,3-benzoxazine-2,4-dione

1.11 g of 60% sodium hydride (suspended in mineral oil) is suspended in 80 ml of N, N-dimethylacetamide and 5.00 g of 6-chloro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione are added in portions . The resulting mixture was stirred at room temperature for one hour, and 4.81 ml of ethyl 5-bromovalerate was added. The resulting mixture was stirred at 50 ^° C. for 24 hours, poured into 200 ml of a mixture of 1N hydrochloric acid and ice and extracted with ethyl acetate. The organic phase is washed with water and brine, dried with anhydrous magnesium sulfate and the solvent is distilled off. Ether is either added to the resulting solid residue. The resulting mixture was filtered and obtain 4.89 g of the target compound as a pale yellow powder, yield 60%.

Mp 97-99 ^o C (faint yellow needles from n-hexane / ethyl acetate).

Бледно-желтый порошок получен с выходом 60%.NMR (400 MHz, δ, CDCl ₃ ):
1.25 (t, J = 7.1 Hz, 3H), 1.72 - 1.86 (m, 4H), 2.40 (t, J = 7.0 Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H), 4.13 (k, J = 7.1 Hz, 2H), 7.17 (d, J = 9.0 Hz, 1H), 7.71 (dd, J = 2.6, 9.0 Hz, 1H), 8.12 (d, J = 2.6 Hz, 1H)
Preparative example 7
6-Chloro-1- [3- (ethoxycarbonyl) propyl] -1,2-dihydro-4H-1,3-benzoxazine-2,4-dione

A pale yellow powder was obtained in 60% yield.

Слабо-желтый порошок получен с выходом 89%
Т.пл. 214-217^oC
(белые иглы из EtOAc).Mp 78-80 ^o C
(pale yellow prisms from n-hexane / ethyl acetate)
NMR (400 MHz, δ CDCl ₃ ):
1.30 (t, J = 7.1 Hz, 3H), 1.99 - 2.09 (m, 2H), 2.51 (t, J = 6.2 Hz, 2H), 4.12 (t, J = 8.1 Hz, 2H), 4.19 (k, J = 7.1 Hz, 2H), 7.52 (d, J = 9.0 Hz, 1H), 7.75 (dd, J = 2.4, 9.0 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H)
Preparative example 8
6-Chloro-1- (4-methoxycarbonylbenzyl) -1,2-dihydro-4H-1,3-benzoxazine-2,4-dione

Light yellow powder obtained in 89% yield.
Mp 214-217 ^o C
(white needles from EtOAc).

2-Амино-5-бромбензойную кислоту (15.59 г), 4-метоксибензиловый спирт (7.5 мл), 1,3-дициклогексилкарбодиимид (14.89 г) и 4-диметиламинопиридин (8.07 г) добавляют к 200 мл ацетонитрила. Полученную смесь перемешивают при комнатной температуре 18 ч и нерастворимый материал отфильтровывают. Фильтрат концентрируют в вакууме, добавляют воду и образующуюся смесь экстрагируют этилацетатом. Этилацетную фазу последовательно промывают водой, 1H соляной кислотой, водой, 1H гидроксидом натрия, водой и насыщенным водным раствором соли, сушат над сульфатом магния и растворитель отгоняют в вакууме. Остаток очищают колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 8:1 до 5:1)), выход 65%.NMR (400 MHz, δ, CDCl ₃ ):
3.91 (s, 3H), 6.97 (d, J = 9.0 Hz, 1H), 7.33 - 7.38 (m, 2H), 7.57 (dd, J = 2.6, 9.0 Hz, 1H), 8.02 - 8.06 (m, 2H) , 8.14 (d, J = 2.6 Hz)
Preparative example 9
4-methoxybenzyl-2-amino-5-bromobenzoate

2-amino-5-bromobenzoic acid (15.59 g), 4-methoxybenzyl alcohol (7.5 ml), 1,3-dicyclohexylcarbodiimide (14.89 g) and 4-dimethylaminopyridine (8.07 g) are added to 200 ml of acetonitrile. The resulting mixture was stirred at room temperature for 18 hours and the insoluble material was filtered off. The filtrate was concentrated in vacuo, water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed successively with water, 1H hydrochloric acid, water, 1H sodium hydroxide, water and brine, dried over magnesium sulfate and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (8: 1 to 5: 1)), yield 65%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.82 (3H, s), 5.24 (2H, s), 5.76 (2H, sh s), 6.54 (1H, d, J = 8.8 Hz), 6.92 (2H, m), 7.30 (1H, dd, J = 8.8 , 2.6 Hz), 7.37 (2H, m), 7.96 (1H, d, J = 2.6 Hz).

2-Амино-5-цианобензойную кислоту (32.18 г), 4-метоксибензилхлорид (28.34 мл) и безводный карбонат калия (28.89 г) добавляют к 400 мл N,N-димeтилфopмaмидa. Полученную смесь перемешивают при комнатной температуре 15 часов, добавляют ледяную воду и экстрагируют этилацетатом. Этилацетатную фазу промывают последовательно водой, 1H соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушат над безводным сульфатом магния и растворитель отгоняют в вакууме. Остаток очищают колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 4: 1 до 3:1)). Полученный твердый материал промывают смесью н-гексан/этилацетат и получают 28.92 г указанного в заголовке соединения в виде бледно-желтого порошка, выход 52%.Preparative example 10
4-methoxybenzyl-2-amino-5-cyanobenzoate

2-amino-5-cyanobenzoic acid (32.18 g), 4-methoxybenzyl chloride (28.34 ml) and anhydrous potassium carbonate (28.89 g) are added to 400 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 15 hours, ice water was added and extracted with ethyl acetate. The ethyl acetate phase was washed sequentially with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (4: 1 to 3: 1)). The resulting solid was washed with n-hexane / ethyl acetate to give 28.92 g of the title compound as a pale yellow powder, yield 52%.

Mp 120-122 ^o C.

Mass .: 283 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.83 (3H, s), 5.26 (2H, s), 6.30 (2H, sh s), 6.65 (1H, d, J = 8.6 Hz), 6.91 - 6.98 (2H, m), 7.35 - 7.40 (2H, m ), 7.43 (1H, dd, J = 8.6, 2.0 Hz), 8.19 (1H, d, J = 2.0 Hz).

4-Метоксибензил-2-амино-5-бромбензоат (13.13 г) и 1,1'- карбонилдиимидазол (6.97 г) добавляют к 100 мл тетрагидрофурана. Полученную смесь нагревают при кипячении с обратным холодильником 41 ч, оставляют охлаждаться и затем добавляют 6.63 мл этилизонипекотата. Полученную смесь перемешивают при комнатной температуре один час и концентрируют в вакууме. Остаток очищают колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3: 1)) и получают 4.40 г указанного в заголовке соединения в виде бледно-желтого твердого вещества, выход 20%.Preparative example 11
Ethyl 1 - [[4-bromo-2 - [(4-methoxybenzyloxy) carbonyl] phenyl] - carbamoyl] piperidine-4-carboxylate

4-Methoxybenzyl-2-amino-5-bromobenzoate (13.13 g) and 1,1'-carbonyldiimidazole (6.97 g) are added to 100 ml of tetrahydrofuran. The resulting mixture was heated at reflux for 41 hours, allowed to cool, and then 6.63 ml of ethyl isonipecotate was added. The resulting mixture was stirred at room temperature for one hour and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)) to obtain 4.40 g of the title compound as a pale yellow solid, 20% yield.

Mp 98-100 ^o C.

Mass .: 520 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.76 (2H, m), 2.01 (2H, m), 2.55 (1H, m), 3.07 (2H, m), 3.83 (3H, s), 4.12 (2H , m), 4.17 (2H, k, J = 7.1 Hz), 5.28 (2H, s), 6.94 (2H, m), 7.38 (2H, m), 7.56 (1H, dd, J = 9.2, 2.6 Hz) 8.09 (1H, d, J = 2.6 Hz), 8.46 (1H, d, J = 9.2 Hz), 10.69 (1H, s).

Указанное в заголовке соединение получают как в Препаративном примере 3 в виде белого твердого вещества, выход 4%.Example 12
1 - [[4-Chloro-2 - [(4-methoxybenzyloxy) carbonyl] phenyl] - carbamoyl] -4-hydroxypiperidine

The title compound was obtained as in Preparation Example 3 as a white solid, 4% yield.

Mp 112-114 ^o C.

Mass .: 419 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.55 - 1.65 (3H, m), 1.98 (2H, m), 3.27 (2H, ddd, J = 13.7, 9.2, 3.3 Hz), 3.83 (3H, s), 3.91 - 4.00 (3H, m), 5.28 ( 2H, s), 6.91 - 6.96 (2H, m), 7.35 - 7.40 (2H, m), 7.43 (1H, dd, J = 9.2, 2.6 Hz), 7.95 (1H, d, J - 2.6 Hz), 8.52 (1H, d, J = 9.2 Hz), 10.69 (1H, s).

Указанное в заголовке соединение получают, как в Препаративном примере 3, в виде белого твердого вещества, выход 4%.Preparative example 13
1 - [[4-Cyano-2 - [(4-methoxybenzyloxy) carbonyl] phenyl] carbamoyl] - 4-hydroxypiperidine

The title compound was obtained, as in Preparation Example 3, as a white solid, 4% yield.

Mp 167-169 ^o C.

Mass .: 410 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.56 - 1.67 (3H, m), 1.99 (2H, m), 3.33 (2H, ddd, J - 13.7, 9.0, 3.5 Hz), 3.84 (3H, s), 3.91 - 4.03 (3H, m), 5.31 ( 2H, s), 6.92 - 6.97 (2H, m), 7.35 - 7.40 (2H, m), 7.69 (1H, dd, J = 9.0, 2.2 Hz), 8.30 (1H, d, J = 2.2 Hz), 8.69 (1H, d, J = 9.0 Hz), 11.04 (1H, s).

Смесь, содержащую 3.82 г этил-1-[[4-бром-2-[(4- метоксибензилокси)карбонил] фенил]карбамоил]пиперидин-4-карбоксилата, 4.02 мл анизола и 5.7 мл трифторуксусной кислоты, перемешивают при комнатной температуре 2.5 ч и концентрируют в вакууме. К остатку добавляют водный раствор карбоната натрия и эфир для отделения водной фазы. Эфирную фазу экстрагируют водным раствором карбоната натрия. Обе водные фазы объединяют и промывают эфиром. Полученную водную фазу подкисляют концентрированной соляной кислотой, что дает осадок. Осадок отделяют фильтрованием и получают 2.50 г целевого соединения в виде белого порошка, выход 85%.Preparative example 14
Ethyl 1 - [(4-bromo-2-carboxyphenyl) carbamoyl] piperidine-4-carboxylate

A mixture containing 3.82 g of ethyl 1 - [[4-bromo-2 - [(4-methoxybenzyloxy) carbonyl] phenyl] carbamoyl] piperidine-4-carboxylate, 4.02 ml of anisole and 5.7 ml of trifluoroacetic acid was stirred at room temperature for 2.5 hours and concentrated in vacuo. An aqueous solution of sodium carbonate and ether are added to the residue to separate the aqueous phase. The ether phase is extracted with an aqueous solution of sodium carbonate. Both aqueous phases are combined and washed with ether. The resulting aqueous phase is acidified with concentrated hydrochloric acid, which gives a precipitate. The precipitate was separated by filtration to obtain 2.50 g of the target compound in the form of a white powder, yield 85%.

Mp 153-155 ^o C (decomp.).

Mass .: 399 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.28 (3H, t, J = 7.1 Hz), 1.77 (2H, m), 2.02 (2H, m), 2.58 (1H, m), 3.09 (2H, m), 4.11 (2H, m), 4.18 (2H , k, J = 7.1 Hz), 7.61 (1H, dd, J = 9.2, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.42 (1H, d, J = 9.2 Hz), 10.67 (1H , with).

Указанное в заголовке соединение получают, как в Препаративном примере 6, в виде белого твердого вещества, выход 77%.Preparative example 15
1 - [(2-Carboxy-4-chlorophenyl) carbamoyl] -4-hydroxypiperidine

The title compound was obtained, as in Preparation Example 6, as a white solid, yield 77%.

Mp 168-170 ^o C (decomp.).

Mass .: 299 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.36 (2H, m), 1.78 (2H, m), 3.16 (2H, ddd, J = 13.5, 9.5, 3.1 Hz), 3.67 - 3.83 (3H, m), 7.57 (1H, dd, J = 9.2, 2.7 Hz), 7.89 (1H, d, J = 2.7 Hz), 8.43 (1H, d, J = 9.2 Hz), 10.85 (1H, s).

Указанное в заголовке соединение получают, как в Препаративном примере 6, в виде белого твердого вещества, выход 77%.Preparative example 16
1 - [(2-Carboxy-4-cyanophenyl) carbamoyl] -4-hydroxypiperidine

The title compound was obtained, as in Preparation Example 6, as a white solid, yield 77%.

Mp 175-179 ^o C (decomp.).

Mass: 290 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.37 (2H, m), 1.78 (2H, m), 3.19 (2H, ddd, J = 13.2, 9.3, 3.5 Hz), 2.68 - 3.82 (3H, m), 7.93 (1H, dd, J = 9.0, 2.2 Hz), 8.30 (1H, d, J = 2.2 Hz), 8.55 (1H, d, J = 9.0 Hz), 11.23 (1H, s).

Метил-2-амино-4-метоксибензоат (8.44 г) и карбонат кальция (5.13 г) растворяли в смешанном растворителе, содержащем 250 мл дихлорметана и 100 мл метанола, и порциями добавляют 19.09 г бензилтриметиламмонийтрибромида. Полученную смесь перемешивают при комнатной температуре один час и отфильтровывают нерастворимый материал. Фильтрат концентрируют в вакууме, к остатку добавляют этилацетат и смесь фильтруют через силикагель. Фильтрат концентрируют в вакууме и остаток очищают колоночной хроматографией на силикагеле (растворитель н-гексан/этилацетат (4:1)). Полученный твердый материал промывают н-гексаном и получают 10.37 г указанного в заголовке соединения в виде бледно-желтого твердого вещества, выход 86%.Preparative example 17
Methyl 2-amino-5-bromo-4-methoxybenzoate

Methyl 2-amino-4-methoxybenzoate (8.44 g) and calcium carbonate (5.13 g) were dissolved in a mixed solvent containing 250 ml of dichloromethane and 100 ml of methanol, and 19.09 g of benzyltrimethylammonium tribromide was added in portions. The resulting mixture was stirred at room temperature for one hour and insoluble material was filtered off. The filtrate was concentrated in vacuo, ethyl acetate was added to the residue, and the mixture was filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate (4: 1)). The resulting solid was washed with n-hexane to give 10.37 g of the title compound as a pale yellow solid, 86% yield.

Mp 104-105 ^o C.

Mass: 260 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.84 (3H, s), 3.87 (3H, s), 5.85 (2H, s, s), 6.12 (1H, s), 8.01 (1H, s).

Метил-2-бромметил-5-нитробензоат (6.59 г) суспендировали в 130 мл метанола. Через полученную суспензию пропускали большой избыток аммиака при комнатной температуре. Полученную смесь перемешивали при комнатной температуре 20 ч и концентрировали в вакууме. К остатку добавляли воду, нерастворимый материал отфильтровывали и промывали эфиром. Указанное в заголовке соединение получали в виде слабо-желтого порошка, выход 90%.Preparative example 18
7-nitroisoindolin-1-one

Methyl 2-bromomethyl-5-nitrobenzoate (6.59 g) was suspended in 130 ml of methanol. A large excess of ammonia was passed through the resulting suspension at room temperature. The resulting mixture was stirred at room temperature for 20 hours and concentrated in vacuo. Water was added to the residue, insoluble material was filtered off and washed with ether. The title compound was obtained as a slightly yellow powder, yield 90%.

Mp 218-221 ^o C.

Mass: 179 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.48 (2H, s), 7.80 (1H, dd, J = 7.7, 7.3 Hz), 7.87 (1H, d, J = 7.3 Hz), 7.88 (1H, d, J = 7.7 Hz), 8.98 (1H, w with).

7-Hитроизоиндолинон (6.52 г) суспендировали в 1000 мл тетрагидрофурана, добавляли 1 г 10% палладия на угле (водосодержащий). Полученную смесь подвергали каталитическому восстановлению в условиях комнатной температуры и 1 атм. Через 18 ч катализатор отфильтровывали и фильтрат концентрировали в вакууме. Полученное твердое вещество промывали эфиром и получали 5.13 г целевого соединения в виде слабо-желтого порошка, выход 95%.Preparative example 19
7-aminoisoindolin-1-one

7-Nitroisoindolinone (6.52 g) was suspended in 1000 ml of tetrahydrofuran, 1 g of 10% palladium-carbon (water-containing) was added. The resulting mixture was subjected to catalytic reduction at room temperature and 1 atm. After 18 hours, the catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting solid was washed with ether and 5.13 g of the target compound was obtained in the form of a slightly yellow powder, yield 95%.

Mp 153-155 ^o C.

Mass: 149 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.36 (2H, s), 5.21 (2H, s s), 6.57 (1H, d, J = 8.1 Hz), 6.70 (1H, d, J = 7.3 Hz ), 6.72 (1H, br s), 7.27 (1H, dd, J = 8.1, 7.3 Hz).

Метил-2-бромметил-5-нитробензоат (11.64 г) суспендировали в 200 мл метанола и добавляли раствор 2.19 г цианида натрия в 20 мл воды. Полученную смесь перемешивали 3 ч при 50^oC и концентрировали в вакууме. К остатку добавляли воду и смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 3:1 до 2: 1)). Полученный твердый материал промывали н-гексаном и получали 5.43 г указанного в заголовке соединения в виде белого твердого вещества, выход 58%.Preparative example 20
Methyl 2-cyanomethyl-6-nitrobenzoate

Methyl 2-bromomethyl-5-nitrobenzoate (11.64 g) was suspended in 200 ml of methanol and a solution of 2.19 g of sodium cyanide in 20 ml of water was added. The resulting mixture was stirred for 3 hours at 50 ^° C. and concentrated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1 to 2: 1)). The resulting solid was washed with n-hexane to give 5.43 g of the title compound as a white solid, yield 58%.

Mp 103-105 ^o C.

Mass: 221 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.91 (2H, s), 3.98 (3H, s), 7.68 (lH, t, J = 8.1 Hz), 7.87 (1H, dd, J = 8.1, 1.1 Hz), 8.11 (1H, dd, J = 8.1, 1.1 Hz).

Метил-2-цианометил-5-нитробензоат (54.43 г) суспендируют в 200 мл метанола и добавляют 4.5 мл концентрированной соляной кислоты и 0.18 г оксида платины. Полученную смесь подвергали каталитическому восстановлению при комнатной температуре и давлении 3 кг/см². Через 7 ч катализатор отфильтровывали и фильтрат концентрировали в вакууме.Preparative example 21
8-amino-1,2,3,4-tetrahydro-1-isoquinolinone

Methyl 2-cyanomethyl-5-nitrobenzoate (54.43 g) is suspended in 200 ml of methanol and 4.5 ml of concentrated hydrochloric acid and 0.18 g of platinum oxide are added. The resulting mixture was subjected to catalytic reduction at room temperature and a pressure of 3 kg / cm ² . After 7 hours, the catalyst was filtered off and the filtrate was concentrated in vacuo.

 The residue was dissolved in 50 ml of methanol and 7.50 g of anhydrous potassium carbonate was added. The resulting mixture was refluxed for 9.5 h and an insoluble precipitate was filtered off. The filtrate was concentrated in vacuo and water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)), and 0.75 g of the title compound was obtained as a white powder, yield 19%.

Mp 128-130 ^o C.

Mass: 163 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.90 (2H, t, J = 6.6 Hz), 3.47 (1H, dt, J = 6.6, 2.9 Hz), 5.98 (1H, sh s), 6.05 (2H, sh s), 6.43 (1H, dd, J = 7.3, 1.1 Hz), 6.52 (IH, dd, J = 8.3, 1.1 Hz), 7.12 (1H, dd, J = 8.1, 7.3 Hz).

Указанное в заголовке соединение получают, как в Препаративном примере 9, в виде белого порошка, выход 62%.Preparative example 22
7-amino-4-bromisoindolinone

The title compound was obtained, as in Preparation Example 9, as a white powder, yield 62%.

Mp 253-258 ^° C (decomp.).

Mass: 227 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.12 (2H, s), 6.20 (2H, s s), 6.56 (1H, d, J = 8.6 Hz), 7.32 (1H, D, J = 8.6 Hz), 8.38 (1H, s s).

Указанное в заголовке соединение получают, как в Препаративном примере 9, в виде белого порошка, выход 66%.Example 23
5-bromo-8-aminoisoquinolin-1-one

The title compound was obtained, as in Preparation Example 9, as a white powder, yield 66%.

Mp 158-160 ^o C (decomp.).

Mass: 241 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.01 (2H, t, J = 6.6 Hz), 3.48 (2H, dt, J = 6.6, 2.9 Hz), 6.13 (2H, sh s), 6.19 (1H, sh s), 6.45 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 8.8 Hz).

Метил- 2-амино-5-бромбензоат (5.00 г) растворяли в 10 мл N-метил-2-пирролидона и добавляли 2.14 г цианида меди(I). Полученную смесь перемешивали при 180^oC 4 ч и добавляли водный раствор этилендиамина. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 3:1 до 2:1)) Полученный твердый материал промывали н-гексаном и получали 2.84 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 74%.Example 24
Methyl 2-amino-5-cyanobenzoate

Methyl 2-amino-5-bromobenzoate (5.00 g) was dissolved in 10 ml of N-methyl-2-pyrrolidone and 2.14 g of copper (I) cyanide was added. The resulting mixture was stirred at 180 ^° C. for 4 hours and an aqueous solution of ethylene diamine was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with an aqueous salt solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1 to 2: 1)). The obtained solid material was washed with n-hexane to obtain 2.84 g of the title compound as a slightly yellow powder, yield 74% .

Mp 127-130 ^o C.

Mass: 177 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 6.30 (2H, ws), 6.67 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.6, 2.0 Hz), 8.20 (1H, d, J = 2.0 Hz).

Метил-2-амино-5-цианобензоат (2.84 г) растворяли в 60 мл этанола и добавляли 24 мл 1H гидроксида натрия. Полученную смесь перемешивали при комнатной температуре 6 ч и концентрировали в вакууме. К остатку добавляли воду и эфир и водную фазу отделяли. Эфирную фазу экстрагировали водой. Обе водные фазы объединяли и подкисляли концентрированной соляной кислотой до выпадения осадка. Осадок отделяли фильтрованием и получали указанное в заголовке соединение в виде белого порошка, выход 98%.Preparative example 25
2-amino-5-cyanobenzoic acid

Methyl 2-amino-5-cyanobenzoate (2.84 g) was dissolved in 60 ml of ethanol and 24 ml of 1H sodium hydroxide was added. The resulting mixture was stirred at room temperature for 6 hours and concentrated in vacuo. Water and ether were added to the residue, and the aqueous phase was separated. The ether phase was extracted with water. Both aqueous phases were combined and acidified with concentrated hydrochloric acid until a precipitate formed. The precipitate was collected by filtration to obtain the title compound as a white powder, yield 98%.

Mp 268-272 ^o C.

Mass: 163 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
6.85 (1H, d, J = 8.8 Hz), 7.49 (2H, sh s), 7.55 (1H, dd, J = 8.8, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz).

Этил-2-амино-5-(1,2,4-триазол-1-ил)бензоат (2.00 г) суспендировали в 15 мл этанола и добавляли 9.2 мл 1H гидроксида натрия. Полученную смесь перемешивали при 65^oC 1 ч и концентрировали в вакууме. К остатку добавляли воду и смесь подкисляли концентрированной соляной кислотой до выпадения осадка. Осадок отделяли фильтрованием и получали 2.55 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 100%.Preparative example 26
2-amino-5- (1,2,4-triazol-1-yl) benzoic acid

Ethyl 2-amino-5- (1,2,4-triazol-1-yl) benzoate (2.00 g) was suspended in 15 ml of ethanol and 9.2 ml of 1H sodium hydroxide was added. The resulting mixture was stirred at 65 ^° C. for 1 hour and concentrated in vacuo. Water was added to the residue, and the mixture was acidified with concentrated hydrochloric acid until a precipitate formed. The precipitate was collected by filtration to obtain 2.55 g of the title compound as a slightly yellow powder, yield 100%.

Mp 229-231 ^o C.

Mass: 235 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ):
8.24 - 8.27 (2H, m), 8.34 (1H, m), 8.36 (1H, s), 9.57 (1H, s).

Указанное в заголовке соединение получали, как в Препаративном примере 18, в виде слабо-желтого порошка, выход 100%
Т.пл. 246-248^oC.Preparative example 27
2-amino-5- (1-pyrazolyl) benzoic acid

The title compound was obtained, as in Preparation Example 18, as a slightly yellow powder, yield 100%
Mp 246-248 ^o C.

Mass: 234 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ δ:
6.67 (1H, dd, J = 2.6, 1.8 Hz), 7.90 (1H, d, J = 1.8 Hz), 8.18 - 8.24 (2H, m), 8.27 (1H, m), 8.79 (1H, d, J = 2.6 Hz).

Указанное в заголовке соединение получали, как в Препаративном примере 17, в виде слабо-желтого порошка, выход 97%.Preparative example 28
2-amino-5-bromo-4-methoxybenzoic acid

The title compound was obtained, as in Preparation Example 17, as a slightly yellow powder, yield 97%.

Mp 198 ^o C (decomp.).

Mass: 245 (MH ⁺ ).

2-Амино-5-хлор-N-(3-хлор-4- метоксибензил)бензамид (1.74 г) растворяли в 18 мл тетрагидрофурана, добавляли 0.82 мл триэтиламина. При охлаждении льдом прибавляли по каплям хлорацетилхлорид (0.47 мл). Полученную смесь перемешивали при комнатной температуре 2 ч и добавляли воду. Выпавший осадок отделяли фильтрованием, промывали водой и эфиром и получали 1.77 г указанного в заголовке соединения в виде слабо-кремового порошка, выход 82%. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ:
3.80 (3H, s), 6.42 (1H, s), 7.71 (1H, s)
Preparative example 29
5-Chloro-2-chloroacetamido-N- (3-chloro-4-methoxybenzyl) benzamide

2-amino-5-chloro-N- (3-chloro-4-methoxybenzyl) benzamide (1.74 g) was dissolved in 18 ml of tetrahydrofuran, 0.82 ml of triethylamine was added. Under ice cooling, chloroacetyl chloride (0.47 ml) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours and water was added. The precipitate was separated by filtration, washed with water and ether, and 1.77 g of the title compound was obtained as a weak cream powder, yield 82%.

Mp 174-176 ^o C.

Mass: 401 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.91 (3H, s), 4.18 (2H, s), 4.54 (2H, d, J = 5.9 Hz), 6.55 (1H, m), 6.92 (1H, d, J = 8.4 Hz), 7.22 (1H, dd , J = 8.4, 2.2 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.41 (IH, dd, J = 8.8, 2.4 Hz), 7.44 (IH, d, J = 2.4 Hz), 8.53 (1H d, J = 8.8 Hz), 11.71 (1H, br s).

Указанное в заголовке соединение получали, как в Препаративном примере 21, в виде слабо-оранжевого порошка, выход 95%.Preparative example 30
2- (4-Bromopropionylamino) -5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Preparation Example 21, as a slightly orange powder, yield 95%.

Mp 170-171 ^o C.

Mass: 439 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.88, 3.00 (total 2H, t, J = 6.8 Hz), 3.69, 3.87 (total 2H, t, J = 6.8 Hz), 4.50 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.49 (1H, w m), 6.79 (1H, d, J = 7.9 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.83 (1H, s), 7.41 (1H, d, J = 2.4 Hz), 7.41 (1H, dd, J = 9.5, 2.4 Hz), 8.57 (1H, d, J = 9.5 Hz), 11.12 (1H, w s).

Указанное в заголовке соединение получают, как в Препаративном примере 21, в виде слабо-охристого порошка, выход 90%.Preparative example 31
2- (4-Bromobutyrylamino) -5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Preparation Example 21, as a slightly ocher powder, 90% yield.

Mp 158-159 ^o C.

Mass: 455 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.28 (2H, t, J = 7.1, 6.4 Hz), 2.61 (2H, t, J = 7.1 Hz), 3.52 (2H, t, J = 6.4 Hz), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.46 (1H, m), 6.78 - 6.86 (3H, m), 7.40 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 9.5, 2.4 Hz), 8.56 (1H, d, J = 9.5 Hz), 11.02 (1H, w s).

Моноэтиловый эфир транс-1,4-циклогександикарбоновой кислоты (10.00 г) растворяли в 200 мл трет-бутанола, добавляли 7.67 мл триэтиламина и 11.85 мл дифенилфосфорилазида. Полученную смесь кипятили с обратным холодильником 7 ч, концентрировали и добавляли воду. Образующуюся смесь экстрагировали этилацетатом. Органическую фазу промывали 1H соляной кислотой, водой, 1H гидроксидом натрия и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 8:1 до 4: 1)) и получали 5.36 г указанного в заголовке соединения в виде белого твердого вещества, выход 40%.Preparative example 32
Ethyl trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylate

Trans-1,4-cyclohexanedicarboxylic acid monoethyl ester (10.00 g) was dissolved in 200 ml of tert-butanol, 7.67 ml of triethylamine and 11.85 ml of diphenylphosphorylazide were added. The resulting mixture was refluxed for 7 hours, concentrated and water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water, 1N sodium hydroxide and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (8: 1 to 4: 1)), and 5.36 g of the title compound was obtained as a white solid, yield 40%.

Mp 89-91 ^o C.

Mass: 270 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.11 (2H, m), 1.25 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 1.52 (2H, m), 1.96 - 2.15 ( 4H, m), 2.20 (1H, dt, J = 12.3, 3.5 Hz), 3.41 (1H, sh s), 4.11 (2H, k, J = 7.1 Hz), 4.39 (1H, sh s).

Этил-транс-4-(третбутоксикарбониламино)циклогексанкарбоксилат (5.36 г) и 1,5-дибромбутан (13.5 мл) растворяли в 50 мл N.N-диметилформамида и добавляли 0.87 г 60% гидрида натрия. Полученную смесь перемешивали при 50^oC 5 ч и выливали в воду со льдом. Смесь экстрагировали этилацетатом. Органическую фазу промывали 1H соляной кислотой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 10:1 до 5:1)) и получали 4.32 г указанного в заголовке соединения в виде бесцветного масла, выход 52%.Preparative example 33
Ethyl trans-4- [K- (5-bromobutyl) -N- (tert-butoxycarbonyl) amino] cyclohexanecarboxylate

Ethyl trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylate (5.36 g) and 1,5-dibromobutane (13.5 ml) were dissolved in 50 ml of NN-dimethylformamide and 0.87 g of 60% sodium hydride was added. The resulting mixture was stirred at 50 ^° C. for 5 hours and poured into ice water. The mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and saturated aqueous brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (10: 1 to 5: 1)), and 4.32 g of the title compound was obtained as a colorless oil, yield 52%.

Mass: 420 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.25 (3H, t, J = 7.1 Hz), 1.35 - 1.60 (17H, m), 1.99 - 2.12 (2H, m), 2.19 (1H, m), 3.05 (2H, w s), 3.41 (2H, t , J - 6.8 Hz), 3.86 (1H, br s), 4.12 (2H, q, J = 7.1 Hz).

Этил-трант-4-[N-(5-бромбутил)-N-(трет-бутоксикарбонил)- амино] циклогексанкарбоксилат (5.92 г) растворяли в 20 мл хлороформе и добавляли 18 мл 4H соляной кислоты/этилацетата. Полученную смесь перемешивали при комнатной температуре 14 ч и концентрировали. Остаток растворяли в 30 мл этанола и добавляли 5.85 г безводного карбоната калия. Полученную смесь перемешивали при комнатной температуре 3 ч, затем 6 ч при 80^oC и добавляли Целит. Hерастворимый материал отфильтровывали и фильтрат концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол/концентрированный водный аммиак (1000:100:2)) и получали 1.91 г указанного в заголовке соединения в виде бледно-желтого масла, выход 57%.Preparative example 34
Ethyl trans-4-piperidinocyclohexanecarboxylate

Ethyl trans-4- [N- (5-bromobutyl) -N- (tert-butoxycarbonyl) amino] cyclohexanecarboxylate (5.92 g) was dissolved in 20 ml of chloroform and 18 ml of 4H hydrochloric acid / ethyl acetate was added. The resulting mixture was stirred at room temperature for 14 hours and concentrated. The residue was dissolved in 30 ml of ethanol and 5.85 g of anhydrous potassium carbonate was added. The resulting mixture was stirred at room temperature for 3 hours, then for 6 hours at 80 ^° C. and Celite was added. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol / concentrated aqueous ammonia (1000: 100: 2)) to obtain 1.91 g of the title compound as a pale yellow oil, yield 57%.

Mass: 240 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.25 (3H, t, J = 7.1 Hz), 1.28 (2H, m), 1.38 - 1.51 (4H, m), 1.54 - 1.62 (4H, m), 1.95 (2H, m), 2.04 (2H, m) , 2.15 - 2.31 (2H, m), 2.48 - 2.53 (4H, m), 4.11 (2H, q, J = 7.1 Hz).

Этил-транс-4-пиперидиноциклогексанкарбоксилат (1.91 г) растворяли в 20 мл этанола. Полученный раствор перемешивали при комнатной температуре 3 дня, устанавливали pH 7 1H соляной кислотой, концентрировали в вакууме и очищали колоночной хроматографией на ODS (растворитель: вода) и добавляли воду. Нерастворимый осадок отфильтровывали, фильтрат концентрировали в вакууме и добавляли метанол. Нерастворимый осадок отфильтровывали и фильтрат концентрировали в вакууме. Полученный твердый материал промывали эфиром и получали 1.54 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 91%.Example Example 35
trans-4-piperidinocyclohexanecarboxylic acid

Ethyl trans-4-piperidinocyclohexanecarboxylate (1.91 g) was dissolved in 20 ml of ethanol. The resulting solution was stirred at room temperature for 3 days, adjusted to pH 7 with 1N hydrochloric acid, concentrated in vacuo and purified by column chromatography on ODS (solvent: water) and water was added. An insoluble precipitate was filtered off, the filtrate was concentrated in vacuo and methanol was added. An insoluble precipitate was filtered off and the filtrate was concentrated in vacuo. The resulting solid was washed with ether to give 1.54 g of the title compound as a slightly yellow powder, yield 91%.

Mass: 212 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.14 - 1.32 (4H, m), 1.36 (2H, m), 1.41 - 1.49 (4H, m), 1.73 (2H, m), 1.88 (2H, m), 1.96 (1H, m), 2.19 (1H, m), 2.36 - 2.48 (4H, m).

2-Hитро-5-(1-пиразолил)бензойную кислоту (1.40 г), пиперониламин (0.82 мл), хлоргидрат 1-(3-диметиламинопропил)-3-этилкарбодиимида (1.27 г), 1-гидроксибензтриазол (0.89 г) и триэтиламин (0.92 мл) добавляли к 20 мл N, N-диметилформамида. Полученную смесь перемешивали при комнатной температуре 14 ч и добавляли воду. Осадок отделяли фильтрованием и получали 2.19 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 100%.Preparative example 36
N- (3,4-Methylenedioxybenzyl) -2-nitro-5- (1-pyrazolyl) benzamide

2-Nitro-5- (1-pyrazolyl) benzoic acid (1.40 g), piperonylamine (0.82 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.27 g), 1-hydroxybenzotriazole (0.89 g) and triethylamine (0.92 ml) was added to 20 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 14 hours and water was added. The precipitate was collected by filtration to obtain 2.19 g of the title compound as a slightly yellow powder, yield 100%.

Mp 179-180 ^o C.

Mass: 367 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.56 (2H, d, J = 5.5 Hz), 5.95 (2H, s), 6.18 (1H, m), 6.56 (1H, dd, J = 2.6, 1.8 Hz), 6.78 (1H, d, J = 7.9 Hz ), 6.85 (1H, dd, J = 7.9, 1.6 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.78 (1H, d, J = 1.8 Hz), 7.83 (1H, dd, J = 9.0, 2.4 Hz), 7.86 (1H, d, J = 2.4 Hz), 8.01 (1H, d, J = 2.6 Hz), 8.19 (1H, d, J = 9.0 Hz).

Указанное в заголовке соединение получали, как в Препаративном примере 28, в виде порошка цвета бледной охры, выход 84%.Preparative example 37
N- (3,4-Methylenedioxybenzyl) -2-nitro-5- (1,2,4-triazol-1-yl) benzamide

The title compound was obtained, as in Preparation Example 28, as a pale ocher powder, yield 84%.

Mp 187-190 ^o C.

Mass: 368 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.58 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.12 (1H, w), 6.76 (1H, d, J = 7.9 Hz), 6.86 (1H, dd, J = 7.9, 1.7 Hz ), 6.91 (1H, d, J = 1.7 Hz), 7.91 (1H, dd, J = 9.5, 2.6 Hz), 7.91 (1H, d, J = 2.6 Hz), 8.16 (1H, s), 8.27 (1H d, J = 9.5 Hz), 8.69 (1H, s).

Хлор-5-метиланизол (8.00 г), N-бромсукцинимид (9.55 г) и бензоилпероксид (0.62 г) добавляли к 170 мл четыреххлористого углерода. Полученную смесь кипятили с обратным холодильником 1 ч и оставляли охлаждаться. Нерастворимый материал отделяли фильтрованием и фильтрат концентрировали в вакууме. Остаток растворяли в 100 мл N,N-диметилформамида и добавляли 10.41 г фталимида калия. Полученную смесь перемешивали при 50^oC 1 ч и добавляли воду со льдом. Осадок отделяли фильтрованием, промывали водой и эфиром и получали 8.66 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 52%.Preparative example 38
N- (4-Chloro-3-methoxybenzyl) phthalimide

Chloro-5-methylanisole (8.00 g), N-bromosuccinimide (9.55 g) and benzoyl peroxide (0.62 g) were added to 170 ml of carbon tetrachloride. The resulting mixture was refluxed for 1 h and allowed to cool. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 100 ml of N, N-dimethylformamide and 10.41 g of potassium phthalimide was added. The resulting mixture was stirred at 50 ^° C. for 1 hour and ice water was added. The precipitate was filtered off, washed with water and ether to give 8.66 g of the title compound as a slightly yellow powder, yield 52%.

Mp 156-159 ^o C.

Mass: 301 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.80 (2H, s), 6.98 (1H, dd, J = 8.1, 1.8 Hz), 7.05 (1H, d, J = 1.8 Hz), 7.29 (1H, d, J = 8.1 Hz ), 7.69 - 7.75 (2H, m), 7.82-7.88 (2H, m).

2-Метокси-5-пиридинметанол (2.79 г), фталимид (2.92 г) и трифенилфосфин (5.71 г) добавляли к 35 мл тетрагидрофурана. Полученную смесь охлаждали льдом и по каплям добавляли раствор 3.43 г диэтилазодикарбоксилата в 5 мл тетрагидрофурана. Полученную смесь перемешивали при охлаждении льдом 1 ч, затем 15 ч при комнатной температуре и выливали в воду со льдом. Смесь экстрагировали этилацетатом. Органическую фазу промывали 1H соляной кислотой, водой, насыщенным водным раствором гидрокарбонатом натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме и добавляли бензол. Нерастворимый материал отфильтровывали и фильтрат концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3: 1)). Полученное твердое вещество промывали н-гексаном и получали 4.07 г указанного в заголовке соединения в виде белого порошка, выход 77%.Preparative example 39
N - [(2-Methoxy-5-pyridyl) methyl] phthalimide

2-Methoxy-5-pyridinomethanol (2.79 g), phthalimide (2.92 g) and triphenylphosphine (5.71 g) were added to 35 ml of tetrahydrofuran. The resulting mixture was ice-cooled, and a solution of 3.43 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise. The resulting mixture was stirred under ice cooling for 1 hour, then at room temperature for 15 hours and poured into ice water. The mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous brine, dried over anhydrous magnesium sulfate and concentrated in vacuo and benzene was added. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)). The resulting solid was washed with n-hexane to give 4.07 g of the title compound as a white powder, yield 77%.

Mp 122-124 ^o C.

Mass: 269 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.78 (2H, s), 6.99 (1H, d, J = 8.6 Hz), 7.68 (1H, dd, J = 8.6, 2.6 Hz), 7.68 - 7.74 (2H, m), 7.81 - 7.87 (2H, m), 8.27 (1H, d, J = 2.6 Hz).

N-(4-Meтoкcибeнзил)фтaлимид (14.00 г) растворяли в 100 мл трифторуксусной кислоты и по частям добавляли 8.09 г гексаметилентетрамина. Образующуюся смесь перемешивали при комнатной температуре 1 ч, кипятили с обратным холодильником 3.5 ч и добавляли воду со льдом. Смесь экстрагировали этилацетатом. Органическую фазу промывали 1H NaOH и нерастворимый материал отфильтровывали. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и растворитель отгоняли в вакууме. Полученные твердое вещество и вышеуказанный нерастворимый материал объединяли и промывали этилацетатом и получали 13.13 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 85%.Example 40
N- (3-Formyl-4-methoxybenzyl) phthalimide

N- (4-Methoxybenzyl) phthalimide (14.00 g) was dissolved in 100 ml of trifluoroacetic acid and 8.09 g of hexamethylenetetramine was added in portions. The resulting mixture was stirred at room temperature for 1 h, refluxed for 3.5 h, and ice water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with 1N NaOH and the insoluble material was filtered. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was distilled off in vacuo. The resulting solid and the above insoluble material were combined and washed with ethyl acetate to obtain 13.13 g of the title compound as a slightly yellow powder, yield 85%.

Mp 177-179 ^o C.

Mass: 296 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.82 (2H, s), 6.95 (1H, d, J = 8.6 Hz), 7.64 (1H, dd, J = 8.6, 2.4 Hz), 7.69 - 7.74 (2H, m), 7.82 - 7.87 (3H, m), 10.41 (IH, s).

N-(3-Фopмил-4-мeтoкcибeнзил)фтaлимид (12.50 г) суспендировали в 200 мл тетрагидрофурана и добавляли 3.24 г хлоргидрата гидроксиламина, 7.64 г ацетата натрия и 30 мл воды. Смесь перемешивали 30 мин при 60^oC и концентрировали в вакууме. Осадок отделяли фильтрованием, промывали эфиром и получали 11.51 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 88%.Preparative example 41
N- (3-Hydroxyimino-4-methoxybenzyl) phthalimide

N- (3-Formyl-4-methoxybenzyl) phthalimide (12.50 g) was suspended in 200 ml of tetrahydrofuran and 3.24 g of hydroxylamine hydrochloride, 7.64 g of sodium acetate and 30 ml of water were added. The mixture was stirred for 30 minutes at 60 ^° C. and concentrated in vacuo. The precipitate was filtered off and washed with ether to give 11.51 g of the title compound as a slightly yellow powder, 88% yield.

Mp 214-217 ^o C.

Mass: 311 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.25 (1H, w s), 3.82 (3H, s), 4.79 (2H, s), 6.85 (1H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.4 Hz), 7.66 - 7.72 (2H, m), 7.78 (1H, d, J = 2.4 Hz), 7.80 - 7.86 (2H, m), 8.42 (1H, s).

N-(3-Гидpoкcилиминo-4-мeтoкcибeнзил)фтaлимид (11.00 г) суспендировали в 120 мл ксилола и добавляли 3.68 мл уксусного ангидрида. Смесь кипятили с обратным холодильником 14 ч и оставляли охлаждаться. Образующийся осадок отделяли фильтрованием, промывали ксилолом и получали 9.11 г указанного в заголовке соединения в виде белого порошка, выход 88%.Preparative example 42
N- (3-Cyano-4-methoxybenzyl) phthalimide

N- (3-Hydroxylimino-4-methoxybenzyl) phthalimide (11.00 g) was suspended in 120 ml of xylene and 3.68 ml of acetic anhydride was added. The mixture was refluxed for 14 hours and allowed to cool. The precipitate formed was filtered off, washed with xylene and 9.11 g of the title compound was obtained as a white powder, 88% yield.

Mp 205-209 ^o C.

Mass: 293 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.78 (2H, s), 6.92 (1H, m), 7.62 - 7.66 (2H, m), 7.70 - 7.76 (2H, m), 7.83 - 7.88 (2H, m).

N-(4-Хлор-3-метоксибензил)фталимид (8.40 г) и моногидрат гидразина (1.49 мл) добавляли к 100 мл этанола. Смесь кипятили с обратным холодильником 1.5 ч, нерастворимый материал отделяли фильтрованием, фильтрат концентрировали в вакууме и добавляли 1H соляную кислоту. Нерастворимый материал отделяли фильтрованием. Водную фазу промывали эфиром, подщелачивали концентрированным водным аммиаком и экстрагировали эфиром. Эфирную фазу сушили над безводным сульфатом натрия и концентрировали в вакууме. Остаток растворяли в этилацетате и добавляли 4H хлорид водорода/этилацетат. Образующийся осадок отделяли фильтрованием, промывали этилацетатом и получали 4.83 г указанного в заголовке соединения в виде белого порошка, выход 83%.Preparative example 43
4-chloro-3-methoxybenzylamine hydrochloride

N- (4-Chloro-3-methoxybenzyl) phthalimide (8.40 g) and hydrazine monohydrate (1.49 ml) were added to 100 ml of ethanol. The mixture was refluxed for 1.5 hours, insoluble material was separated by filtration, the filtrate was concentrated in vacuo, and 1N hydrochloric acid was added. Insoluble material was separated by filtration. The aqueous phase was washed with ether, made basic with concentrated aqueous ammonia and extracted with ether. The ether phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate and 4N hydrogen chloride / ethyl acetate was added. The precipitate formed was filtered off, washed with ethyl acetate, and 4.83 g of the title compound was obtained as a white powder, yield 83%.

Mp 237-242 ^o C.

Mass: 172 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.88 (3H, s), 4.01 (2H, s), 7.07 (1H, dd, J = 8.0, 1.8 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 1.8 Hz ), 8.57 (3H, br s).

Указанное в заголовке соединение получали, как в Препаративном примере 36, в виде белого порошка, выход 58%.Preparative example 44
5-amino-2-methoxypyridine dihydrochloride

The title compound was obtained, as in Preparation Example 36, as a white powder, yield 58%.

Mp 165 ^o C (decomp.).

Mass: 139 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.87 (3H, s), 3.98 (2H, q, J = 5.9 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.94 (1H, dd, J = 8.4, 2.4 Hz), 8.14 (1H, m ), 8.29 (1H, d, J = 2.4 Hz), 8.58 (2H, br s).

N-(3-Циaнo- 4-мeтoкcибeнзил)фтaлимид (8.60 г) и моногидрат гидразина (1.71 мл) растворяли в смешанном растворителе, содержащем 100 мл этанола и 100 мл 1,4-диоксана. Полученный раствор кипятили с обратным холодильником 2 ч, нерастворимый материал отделяли фильтрованием, концентрировали фильтрат в вакууме и добавляли 1H гидроксида натрия. Образующуюся смесь экстрагировали хлороформом. Органическую фазу сушили над безводным карбонатом калия и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол/концентрированный водный аммиак (100:10:1)) и получали 4.24 г указанного в заголовке соединения в виде слабо-желтого твердого вещества, выход 89%.Example 45
3-cyano-4-methoxybenzylamine

N- (3-Cyano-4-methoxybenzyl) phthalimide (8.60 g) and hydrazine monohydrate (1.71 ml) were dissolved in a mixed solvent containing 100 ml of ethanol and 100 ml of 1,4-dioxane. The resulting solution was refluxed for 2 hours, insoluble material was separated by filtration, the filtrate was concentrated in vacuo, and 1H sodium hydroxide was added. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol / concentrated aqueous ammonia (100: 10: 1)) to obtain 4.24 g of the title compound as a slightly yellow solid, 89% yield.

Mass: 163 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.40 (2H, s), 3.84 (2H, s), 3.92 (3H, s), 6.94 (1H, d, J = 8.4 Hz), 7.49 - 7.54 (2H, m).

(1) 2-Hитро-5-хлорбензойную кислоту (5.0 г), тионилхлорид (3 мл) и 50 мл бензола кипятили с обратным холодильником 4 ч и смесь концентрировали для получения ацилхлорида. Ацилхлорид добавляло к раствору 3.2 мл пиперониламина и 5 мл триэтиламина в ТГФ для проведения реакции. Реакционную смесь обрабатывали обычным способом, продукт перекристаллизовывали из этилацетата и получали 5.8 г 5-хлор-2-нитро-N-(3,4-метилендиоксибензил)бензамида.Example 1
2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide hydrochloride

(1) 2-Nitro-5-chlorobenzoic acid (5.0 g), thionyl chloride (3 ml) and 50 ml of benzene were refluxed for 4 hours and the mixture was concentrated to obtain acyl chloride. Acyl chloride was added to a solution of 3.2 ml of piperonylamine and 5 ml of triethylamine in THF to carry out the reaction. The reaction mixture was treated in the usual way, the product was recrystallized from ethyl acetate, and 5.8 g of 5-chloro-2-nitro-N- (3,4-methylenedioxybenzyl) benzamide was obtained.

NMR (CDCl ₃ ) δ:
4.56 (2H, d, J = 5.7 Hz), 5.97 (2H, s + 1H, bs), 6.80 (1H, d, J = 7.9 Hz), 6.85 (1H, dd, J = 7.9 Hz, 1.8 Hz ), 6.90 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 2.2 Hz), 7.54 (1H, dd, J = 8.6 Hz, 2.2 Hz), 8.05 (1H, d, J = 8.6 Hz).

 (2) 5-Chloro-2-nitro-N- (3,4-methylenedioxybenzyl) benzamide (620 mg), acetic acid (1 ml), water (1 ml) and ethanol (20 ml) were refluxed and added 1.0 g of iron powder in parts with stirring. The mixture was refluxed for 1 h and filtered hot to separate the brown insoluble material. The filtrate was concentrated and ethanol was added. The mixture was heated to dissolve. Concentrated hydrochloric acid was added portionwise, causing the brown solution to turn yellow and clear. Crystallization seed was added to the solution. The mixture was cooled and the crystals were isolated by filtration. The crystals were washed with ethanol and ether, dried, and 520 mg of the title compound was obtained.

Mp 225-228 ^o C (decomp.).

Mass: 305 (M - HCl • H ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
4.32 (2H, d, J-5.6 Hz), 5.07 (3H, bs), 5.98 (2H, s), 6.78 (IH, dd, J = 8.0, 1.2 Hz), 6.84 (1H, d, J = 8.0 Hz ), 6.85 (1H, d, J = 8.8 Hz), 6.89 (1H, d, J = 1.2 Hz), 7.23 (1H, dd, J = 8.8, 2.4 Hz), 7.65 (1H, d, J = 2.4 Hz ), 8.94 (1H, t, J = 5.6 Hz).

2-Амино-5-хлорбензойную кислоту (10.0 г), 3,4-метилендиоксибензиламин (7.62 мл), 1-(3-диметиламинопропил)-3- этил-карбодиимидхлоргидрат (11.74 г), N-гидроксибензтриазол (8.27 г) и триэтиламин (8.53 мл) добавляли к 200 мл ацетонитрила. Смесь перемешивали при комнатной температуре 20 ч, концентрировали и добавляли воду. Образующуюся смесь экстрагировали этилацетатом. Органическую фазу промывали последовательно 1H соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали. Полученное твердое вещество промывали этанолом и получали 14.13 г указанного в заголовке соединения в виде слабо-оранжевого порошка, выход 80%.Example 2
2-amino-5-chlorop-N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-chlorobenzoic acid (10.0 g), 3,4-methylenedioxybenzylamine (7.62 ml), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (11.74 g), N-hydroxybenzotriazole (8.27 g) and triethylamine (8.53 ml) was added to 200 ml of acetonitrile. The mixture was stirred at room temperature for 20 hours, concentrated and water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous brine, dried over anhydrous magnesium sulfate and concentrated. The resulting solid was washed with ethanol to obtain 14.13 g of the title compound as a slightly orange powder, yield 80%.

Mp 142-145 ^o C
(white needles from ethanol).

NMR (400 MHz, CDCl ₃ ) δ:
4.49 (d, J = 5.7 Hz, 2H), 5.48 - 5.58 (w, 2H), 5.96 (s, 2H), 6.22 (w, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.78 (d , J = 7.9 Hz, 1H), 6.81 (dd, J = 0.5, 7.9 Hz, 1H), 6.84 (d, J = 0.5 Hz, 1H), 7.15 (dd, J = 2.4, 8.8 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H).

Example 3
2-amino-5-bromo-N- (3,4-methylenedioxybenzyl) benzamide.

Получали бледно-кремовые иглы, выход 92%.

Received pale cream needles, yield 92%.

Mp 157-158 ^o C
(pale orange-yellow ethanol needles).

NMR (400 MHz, CDCl ₃ ) δ:
4.49 (d, J = 5.7 Hz, 2H), 5.57 (w, 2H), 5.97 (s, 2H), 6.20 (w, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 0.7, 7.9 Hz, 1H), 6.81 (dd, J = 1.3, 7.9 Hz, 1H), 6.84 (dd, J = 0.7, 1.3 Hz, 1H), 7.27 (dd, J = 2.2, 8.8 Hz, 1H) 7.39 (d, J = 2.2 Hz, 1H).

Указанное в заголовке соединение получали в виде бледно-желтого порошка, выход 91%
Т.пл. 122-124^oC
(слабо-желтые иглы из водного этанола
ЯМР (400 МГц, CDCl₃) δ:
2.9 (с, 3H), 4.34 (с, 2H), 4.55 (ш, 2H), 5.96 (с, 2Н), 6.60 - 6.88 (м, 4Н ), 6.66 (д, J = 8.6 Гц), 6.77 (д, J = 7.7 Гц), 7.06 - 7,13 (м, 2H).Example 4
2-amino-5-chloro-n-methyl-n- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained as a pale yellow powder, yield 91%
Mp 122-124 ^o C
(faint yellow needles from water ethanol
NMR (400 MHz, CDCl ₃ ) δ:
2.9 (s, 3H), 4.34 (s, 2H), 4.55 (w, 2H), 5.96 (s, 2H), 6.60 - 6.88 (m, 4H), 6.66 (d, J = 8.6 Hz), 6.77 (d , J = 7.7 Hz), 7.06 - 7.13 (m, 2H).

Метил-2-амино-5-диметиламинометил)бензоат (10.93 г) растворяли в 100 мл этанола и добавляли 63.1 мл 1H гидроксида натрия. Смесь перемешивали при комнатной температуре 14 ч, затем 4 ч при 100^oC и добавляли 63.1 мл 1H соляной кислоты. Полученную смесь концентрировали для получения бледно-желтого порошка.Example 5
2-amino-5-dimethylaminomethyl-N- (3,4-methylenedioxybenzyl) benzamide

Methyl-2-amino-5-dimethylaminomethyl) benzoate (10.93 g) was dissolved in 100 ml of ethanol and 63.1 ml of 1H sodium hydroxide was added. The mixture was stirred at room temperature for 14 hours, then 4 hours at 100 ^° C. and 63.1 ml of 1N hydrochloric acid was added. The resulting mixture was concentrated to obtain a pale yellow powder.

This powder was dissolved in 270 ml of acetonitrile containing 50% water, and 7.19 ml of 3,4-methylenedioxybenzylamine, 11.93 g of 1,3-dicyclohexylcarbodiimide and 7.81 g of N-hydroxybenzotriazole were added. The mixture was stirred for 14 hours at 70 ^° C. and insoluble material was filtered off. Saturated aqueous sodium hydrogen carbonate was added to the filtrate and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; dichloromethane / methanol / concentrated aqueous ammonia 1000: 100: 3) to obtain 15.45 g of the title compound as a pale yellow solid, 90% yield.

NMR (400 MHz, CDCl ₃ ) δ: 2.26 (s, 6H), 3.35 (s, 2H), 4.49 (d, J = 5.9 Hz, 2H), 5.58 (w, 2H), 5.95 (s, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.70 (w, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.82 (dd, J = 1.6, 7.9 Hz, 1H), 6.87 (d , J = 1.6 Hz, 1H), 7.10 (dd, J = 1.6, 8.4 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H).

Этил-1-[(2-карбокси-4-хлорфенил)карбамоил] пиперидин-4- карбоксилат (850 мг), 3,4-метилендиоксибензиламин (0.45 мл), 1,3-дициклогексилкарбодиимид (0.54 г), N-гидрохсибензтриазол (0.36 г) и 4-диметиламинопиридин (каталитическое количество) добавляли к 10 мл диметилформамида. Смесь перемешивали при комнатной температуре 16 ч и добавляли воду и этилацетат. Нерастворимый осадок отделяли фильтрованием, отделяли органическую фазу и промывали ее 1H соляной кислоты, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, сушили над безводным сульфатом магния и растворитель отгоняли. Остаток очищали колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол (30:1)) и получали 1.10 г указанного в заголовке соединения в виде белого твердого вещества, выход 99%.Example 6
Ethyl 1 - [[4-chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylate

Ethyl 1 - [(2-carboxy-4-chlorophenyl) carbamoyl] piperidine-4-carboxylate (850 mg), 3,4-methylenedioxybenzylamine (0.45 ml), 1,3-dicyclohexylcarbodiimide (0.54 g), N-hydroxybenzotriazole ( 0.36 g) and 4-dimethylaminopyridine (catalytic amount) was added to 10 ml of dimethylformamide. The mixture was stirred at room temperature for 16 hours and water and ethyl acetate were added. The insoluble precipitate was separated by filtration, the organic phase was separated and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)) to obtain 1.10 g of the title compound as a white solid, yield 99%.

Mp 153-155 ^o C
(white needles from water ethanol).

NMR (400 MHz, CDCl ₃ ) δ:
1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 1.99 (m, 2H), 2.52 (m, 1H), 3.04 (m, 2H), 4.08 (m, 2H), 4.16 (q , J = 7.1 Hz, 2H), 4.47 (d, J = 5.7 Hz), 5.97 (s, 2H), 6.79 (dd, J = 0.5, 7.9 Hz, 1H), 6.82 (dd, J = 1.5, 7.9 Hz , 1H), 6.86 (dd, J = 0.5, 1.5 Hz, 1H), 7.01 (t, J = 5.7 Hz, 1H), 7.24 (dd, J = 2.6, 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 10.57 (s, 1H).

Белый порошок получали с выходом 96%
Т.пл. 131-132^oC
(белые иглы из EtOH).Example 7
Ethyl 1 - [[4-chloro-2- (3-chloro-4-methoxybenzyl) carbamoyl] phenyl] - carbamoyl] piperidine-4-carboxylate

White powder was obtained in 96% yield.
Mp 131-132 ^o C
(white needles from EtOH).

NMR (400 MHz, DCl ₃ ) δ;
1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 1.99 (m, 2H), 2.52 (m, 1H), 3.05 (m, 1H), 3.91 (s, 3H), 4.08 (m , 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.48 (d, J = 5.7 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 5.7 Hz, 1H ), 7.22 (dd, J = 2.4, 9.0 Hz, 1H), 7.22 (dd, J = 2.2, 8.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 2.2 Hz , 1H), 8.19 (d, J = 9.0 Hz, 1H), 10.54 (s, 1H).

Белый порошок получали с выходом 96%.Example 8
Ethyl 1 - [[4-chloro-2 - [(2,3-dihydrobenzofuran-5-yl) methyl] carbamoyl] - phenyl] piperidine-4-carboxylate

White powder was obtained in 96% yield.

Mp 120-122 ^o C
(white needles from water ethanol).

NMR (400 MHz, CDCl ₃ ) δ:
1.27 (t, J = 7.1 Hz, 3H), 1.75 (m, 2H), 2.00 (m, 2H), 2.52 (m, 1H), 3.05 (m, 2H), 3.22 (t, J = 8.8 Hz, 2H ), 4.10 (m, 2H), 4.16 (K, J = 7.1 Hz, 2H), 4.49 (d, J = 5.5 Hz, 2H), 4.59 (t, J = 8.8 Hz, 2H), 6.69 (t, J = 5.5 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 7.09 (dd, J = 1.8, 8.1 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 2.4, 9.2 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 10.68 (s, 1H).

2-Амино-5-хлор-N-(3,4-метилендиоксибензил)бензамид (1.0 г) растворяли в 10 мл пиридина и добавляли 0.64 г хлоргидрата изоникотиноилхлорида. Смесь перемешивали при комнатной температуре 1 ч, добавляли воду со льдом и экстрагировали этилацетатом. Органическую фазу промывали 1н. соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, последовательно, сушили над безводным сульфатом магния и отгоняли растворитель. Остаток очищали колоночной хроматографией на силикагеле (растворитель; дихлорметан/метанол (50:1)), перекристаллизовывали из этилацетата и получали 630 мг указанного в заголовке соединения в виде белых игл, выход 47%.Example 9
5-Chloro-N- (3,4-methylenedioxybenzyl) -2- (isonicotinoylamino) benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide (1.0 g) was dissolved in 10 ml of pyridine and 0.64 g of isonicotinoyl chloride hydrochloride was added. The mixture was stirred at room temperature for 1 h, ice water was added and extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous salt solution were successively dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; dichloromethane / methanol (50: 1)), recrystallized from ethyl acetate, and 630 mg of the title compound was obtained as white needles, yield 47%.

Mp 204-205 ^o C
(from ethyl acetate).

Mass: (FAB) 410 (MH ⁺ ).

Elemental analysis:
calculated (%): C 61.55, H 3.94, N 10.25;
found (%): C 61.58, H 3.99, N 10.16.

NMR (400 MHz, DMSO-d ₆ ) δ:
4.44, (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.85 (dd, J = 1.5, 8.1 Hz, 1H), 6.87 (dd, J = 0.5, 8.1 Hz, 1H), 6.96 ( dd, J = 0.5, 1.5 Hz, 1H), 7.66 (dd, J = 2.4, 9.0 Hz, 1H), 7.78 - 7.82 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H), 8.60 (d , J = 9.0 Hz, 1H), 8.82 - 8.87 (m, (2H), 9.49 (t, J = 5.9 Hz, 1H), 12.62 (s, 1H).

Получали белые иглы, выход 81%.Example 10
5-Chloro-2- (nicotinoylamino) -N- (3,4-methylenedioxybenzyl) benzamide

Received white needles, yield 81%.

Mp 152-154 ^o C
(ethyl acetate).

Mass: (FAB) 410 (MH ⁺ ).

Elemental analysis:
calculated (%) .: C 61.55, H 3.94, N 10.25;
found (%): C 61.42, H 3.89, N 10.23.

NMR (400 MHz, CDCl ₃ ) δ:
4.54 (d, J = 5.5 Hz, 2H), 5.96 (s, 2H) 6.79 (dd, J = 0.5, 7.9 Hz, 1H), 6.82 (w, 1H), 6.82 (dd, J = 1.6, 7.9 Hz) , 6.85 (dd, J = 0.5, 1.6 Hz, 1H), 7.43 - 7.48 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 8.28 (ddd, J = 1.6, 2.4, 8.1 Hz, 1H ), 8.75 (d, J = 8.8 Hz, 1H), 8.78 (dd, J = 1.6, 4.8 Hz, 1H), 9.26 (dd, J = 0.4, 2.4 Hz, 1H), 12.28 (s, 1H).

2-Амино-5-хлор-N-(3,4- метилендиоксибензил)бензамид (5.00 г) растворяли в 60 мл тетрагидрофурана и добавляли 2.52 мл триэтиламина. Смесь перемешивали при охлаждении льдом. К образующейся смеси по каплям добавляли хлорацетилхлорид (1.44 мл) так, чтобы температура смеси не превышала 10^oC. Через 1 ч добавляли к смеси лед и воду и экстрагировали этилацетатом. Органическую фазу промывали соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, последовательно, сушили над безводным сульфатом магния и отгоняли растворитель. Полученное твердое вещество промывали небольшим количеством этилацетата и получали 5.37 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 86%.Example 11
5-Chloro-2-chloroacetamido-N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide (5.00 g) was dissolved in 60 ml of tetrahydrofuran and 2.52 ml of triethylamine was added. The mixture was stirred under ice cooling. Chloroacetyl chloride (1.44 ml) was added dropwise to the resulting mixture so that the temperature of the mixture did not exceed 10 ^° C. After 1 h, ice and water were added to the mixture and extracted with ethyl acetate. The organic phase was washed with hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous brine, successively, dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting solid was washed with a small amount of ethyl acetate, and 5.37 g of the title compound was obtained as a slightly yellow powder, yield 86%.

Mp 186-187 ^o C
(white needles from ethanol).

NMR (400 MHZ, CDCl ₃ ) δ:
4.18 (s, 2H), 4.52 (d, J = 5.5 Hz, 2H), 5.98 (s, 2H), 6.49 (w, 1H), 6.79 (dd, J = 0.5, 7.9 Hz, 1H), 6.82 (dd , J = 1.6, 7.9 Hz, 1H), 6.85 (dd, J = 0.5, 1.6 Hz, 1H), 7.42 (dd, J = 2.6, 8.6 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H) 8.54 (d, J = 8.6 Hz, 1H); 11.75 (w, 1H).

2-Амино-5-хлор-N-(3,4-метилендиоксибензил)бензамидхлоргидрат (100 мг) вводили в реакцию с 40 мкл ацетилхлорида в 5 мл тетрагидрофурана в присутствии 150 мкл диизопропилэтиламина. Реакционную смесь экстрагировали этилацетатом и водой, продукт перекристаллизовывали из смеси этилацетат/гексан и получали 85 мг целевого соединения с выходом 84%.Example 12
2-Acetamido-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide hydrochloride (100 mg) was reacted with 40 μl of acetyl chloride in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was extracted with ethyl acetate and water, the product was recrystallized from ethyl acetate / hexane, and 85 mg of the target compound was obtained in 84% yield.

Mp 187-188 ^o C
(decomp.).

Mass: 347 (MH ⁺ ).

NMR (400 MHz, CDCl ₃ ) δ:
2.21 (3H, s), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.41 (1H, broad s), 6.81 (2H, s), 6.84 (1H, s), 7.38 - 7.42 (2H, m), 8.57 (1H, d, J = 8.8 Hz), 10.91 (1H, broad s).

Гидрохлорид 2-амино-5-хлор-N-(3,4-метилендиоксибензил)- бензамида (100 мг) вводили в реакцию с 50 мкл фенилхлоркарбоната в 5 мл тетрагидрофурана в присутствии 150 мкл диизопропилэтиламина. Реакционную смесь экстрагировали этилацетатом и водой и подвергали перекристаллизации из смеси этилацетат/гексана и получали 110 мг 5-хлор-N-(3,4-метилендиоксибензил)-2-феноксикарбониламинобензамида, выход 88%.Example 13
5-Chloro-N- (3,4-methylenedioxybenzyl) -2-phenoxycarbonylamino-benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide hydrochloride (100 mg) was reacted with 50 μl of phenylchlorocarbonate in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was extracted with ethyl acetate and water and recrystallized from ethyl acetate / hexane to give 110 mg of 5-chloro-N- (3,4-methylenedioxybenzyl) -2-phenoxycarbonylaminobenzamide, 88% yield.

Mp 149-150 ^o C.

NMR (400 MHz, CDCl ₃ ) δ:
4.54 (2H, d, J = 5.6 Hz), 5.98 (2H, s), 6.41 (1H, w s), 6.80 - 6.87 (3H, m), 7.17 - 7.26 (2H, m), 7.37 - 7.46 (5H , m), 8.38 (1H, d, J = 9.2 Hz), 10.82 (1H, s).

2-Амино-5-хлор-N-(3,4-метилендиоксибензил)бензамид (1.5 г) растворяли в 15 мл пиридина и охлаждали льдом. По каплям добавляли раствор 2.28 г транс-4-этоксикарбонилциклогексан-карбонилхлорида в 5 мл дихлорметана, так чтобы температура реакции не превышала 10^oC. Смесь перемешивали 2 ч, добавляли лед с водой и экстрагировали этилацетатом. Органическую фазу промывали 1н. соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, последовательно, сушили над безводным сульфатом магния и растворитель отгоняли. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3:1)), кристаллизовали из эфира и получали 1.30 г указанного в заголовке соединения в виде бесцветных призм, выход 55%.Example 14
5-Chloro-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] - N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide (1.5 g) was dissolved in 15 ml of pyridine and cooled with ice. A solution of 2.28 g of trans-4-ethoxycarbonylcyclohexane-carbonyl chloride in 5 ml of dichloromethane was added dropwise so that the reaction temperature did not exceed 10 ^° C. The mixture was stirred for 2 hours, ice-water was added and extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of salt were successively dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)), crystallized from ether to give 1.30 g of the title compound as colorless prisms, 55% yield.

Mp 156-158 ^o C
(white needles from water ethanol).

NMR (400 MHz, CDCl ₃ ) δ:
1.26 (t, J = 7.1 Hz, 3H), 1.43 - 1.62 (m, 4H), 2.06 2.14 (m, 4H), 2.22 - 2.36 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.70 (t, J = 5.7 Hz, 1H), 6.76 - 6.85 (m, 3H), 7.32 (dd, J = 2.4, 9.0 Hz , 1H), 7.41 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 9.0, 1H), 11.02 (s, 1H).

Белый порошок получали с выходом 79%.Example 15
5-Bromo-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] - N- (3,4-methylenedioxybenzyl) benzamide

White powder was obtained in 79% yield.

Mp 147-149 ^o C
(white needles from n-Hex / EtOAc).

NMR (400 MHz, CDCl ₃ ) δ:
1.26 (t, J = 7.1 Hz, 3H), 1.44 - 1.53 (m, 4H), 2.07 - 2.15 (m, 4H), 2.25 - 2.37 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H) , 4.51 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.51 (similar, J = 5 Hz, 1H), 6.78 - 6.83 (m, 2H), 6.84 (d, J = 0.9 Hz , 1H), 7.53 (dd, J = 2.4, 8.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 11.02 (s, 1H).

Т.пл. 181-184^oC
(из этилацетата).Example 16
5-Chloro-2 - [[3- (ethoxycarbonyl) acryloyl] amino] -N- (3,4-methylenedioxybenzyl) benzamide

Mp 181-184 ^o C
(from ethyl acetate).

Mass: (FAB) 431 (MH ⁺ ).

Elemental analysis:
calculated (%): C 58.54, H 4.44, N 6.50;
found (%): C 58.44, H 4.41, N 6.49.

NMR (400 MHz, CDCl ₃ ) δ:
1.35 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 4.52 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.53 (m, 1H), 6.78 - 6.86 (m, 3H), 6.90 (d, J = 15.4 Hz, 1H), 7.08 (d, J = 15.4 Hz, 1H), 7.42 - 7.48 (m, 2H), 8.69 (d, J = 9.7 Hz , 1H), 11.57 (s, 1H).

Белые иглы получали с выходом 54%.Example 17
5-Chloro-2 - [[5- (ethoxycarbonyl) valeryl] amino] - N- (3,4-methylene-dioxibenzyl) benzamide

White needles were obtained in 54% yield.

Mp 154-156 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
1.25 (t, J = 7.1 Hz, 3H), 1.67 - 1.81 (m, 4H), 2.35 (t, J = 7.3 Hz, 2H), 2.43 (t, J - 7.0 Hz, 2H), 4.13 (to J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.52 (t, J = 5.7 Hz), 6.75 - 6.87 (m, 3H), 7.37 - 7.42 (m, 2H), 8.57 (d, J = 9.3 Hz, 1H), 10.96 (s, 1H).

Слабо-желтый порошок получали с выходом 73%.Example 18
5-Chloro-2 - [[4- (methoxycarbonyl) benzoyl] amino] -N- (3,4-methylenedioxybenzyl) benzamide

A slightly yellow powder was obtained in 73% yield.

Mp 208-210 ^o C
(white needles from water ethanol).

NMR (400 MHz, DMSO-d ₆ ) δ:
3.90 (s, 3H), 4.42 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.83 (dd, J = 1.5, 7.9 Hz, 1H), 6.86 (dd, J = 0.5, 7.9 Hz ), 6.95 (d, J = 0.5 Hz, 1H), 7.66 (dd, J = 2.6, 9.0 Hz, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.99 - 8.05 (m, 2H), 8.11 - 8.16 (m, 2H), 8.61 (d, J = 9.0 Hz, 1H), 9.47 (t, J = 5.7 Hz), 12.50 (s, 1H).

Белые иглы получали с выходом 44%
Т.пл. 141-142^oC
(из эфира).Example 19
5-Chloro-2 - [(cyclohexanecarbonyl) amino] -N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained with a yield of 44%
Mp 141-142 ^o C
(from the air).

Mass: (FAB) 415 (MH ⁺ ).

Elemental analysis:
calculated (%): C 63.69, H 5.59, N 6.75;
found (%): C 63.47, H 5.60, N 6.65.

NMR (400 MHz, CDCl ₃ ) δ:
1.18 - 1.39 (m, 3H), 1.45 - 1.57 (m, 2H), 1.70 (m, 1H), 1.79 - 1.87 (m, 2H), 1.95 - 2.03 (m, 2H), 2.29 (m, 1H), 4.51 (d, J = 5.5 Hz, 2H), 6.54 (pcs, 1H), 6.77 - 6.83 (m, 2H), 6.84 (m, 1H), 7.37 (dd, J = 2.2, 8.8 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 10.91 (s, 1H).

Слабо-желтые иглы получали с выходом 13%.Example 20
5-Chloro-2 - [(1-methylpiperidin-4-carbonyl) amino] -N- (3,4-methylenedioxybenzyl) beisamide

Light yellow needles were obtained in 13% yield.

Mp 177-178 ^o C
(EtOAc).

Mass: (FAB) 43 (MH ⁺ ).

Elemental analysis:
calculated (%): C 61.47, H 5.63, N 9.77;
found (%): C 61.11, H 5.62, N 9.70.

NMR (400 MHz, CDCl ₃ ) δ:
1.80 - 1.92 (m, 2H), 1.94 - 2.06 (m, 4H), 2.70 (m, 1H), 2.29 (s, 3H), 2.88 - 2.98 (m, 2H), 4.51 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.52 (w, 1H), 6.77 - 6.86 (m, 3H), 7.39 (dd, J = 2.4, 9.7 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H ), 8.60 (d, J = 9.7 Hz, 1H), 11.05 (s, 1H).

Белый порошок получали с выходом 50%.Example 21
5-Dimethylaminomethyl-2 - [[4- (methoxycarbonyl) benzoyl] amino] - N- (3,4-methylenedioxybenzyl) benzamide

White powder was obtained with a yield of 50%.

Mp 171-174 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
2.24 (s, 6H), 3.40 (s, 2H), 3.96 (s, 3H), 4.54 (d, J = 5.7 Hz, 2H), 5.96 (s, 2H), 6.79 (d, J = 7.9 Hz, 1H ), 6.83 (dd, J = 1.5, 7.9 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 6.88 (w, 1H), 7.42 (dd, J = 1.8, 8.4 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 8.08 - 8.13 (m, 2H), 8.15 - 8.21 (m, 2H), 8.76 (d, J = 8.4 Hz, 1H), 12.36 (s, 1H).

Белый порошок получали с выходом 32%.Example 22
5-Dimethylaminomethyl-2 - [[trans-4- (ethoxycarbonyl) - cyclohexanecarbonyl] amino] -N- (3,4-methylenedioxybenzyl) benzamide

White powder was obtained in 32% yield.

Mp 144-145 ^o C.

NMR (400 MHz, CDCl ₃ ) δ:
1.25 (t, J = 7.1 Hz, 3H), 1.43 - 1.64 (m, 4H), 2.05 - 2.13 (m, 4H), 2.20 (s, 6H), 2.24 - 2.35 (m, 2H), 3.35 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 5.95 (s, 2H), 6.77 (dd, J = 0.5, 7.9 Hz, 1H), 6.80 ( dd, J = 1.1, 7.9 Hz, 1H), 6.84 (dd, J = 0.5, 1.1 Hz), 6.86 (t, J = 5.7 Hz, 1H), 7.32 (dd, J = 1.8, 8.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 11.18 (s, 1H).

Белый порошок получали с выходом 82%.Example 23
5-Chloro-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] - amino] -N-methyl-N- (3,4-methylenedioxybenzyl) benzamide

White powder was obtained in 82% yield.

Mp 153-155 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
1.27 (t, J = 7.1 Hz, 3H), 1.41 - 1.62 (m, 4H), 1.96 - 2.35 (m, 6H), 2.88 - 3.08 (w, 3H), 4.14 (q, J = 7.1 Hz, 2H) , 4.45, 4.62 (w, total 2H), 5.98 (w s, 2H), 6.45 - 6.59, 6.71 - 6.93 (w, total 3H), 7.24 (w m, 1H), 7.36 (dd, J = 2.4, 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.80 - 9.01 (w, 1H).

5-Xлop-2-xлopaцeтaмидo-N-(3,4-мeтилeндиoкcибeнзил)бeнзамид (570 мг) растворяли в 5 мл N,N-диметилформамида, добавляли 450 мг 4-гидроксипиперидина, 620 мг карбоната калия и каталитическое количество тетра-(н-бутил)аммонийиодида. Полученную смесь перемешивали при комнатной температуре 1 ч и затем добавляли воду. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над сульфатом магния и растворитель отгоняли. Остаток очищали колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол (30:1)) и перекристаллизовывали из смеси этилацетата/н-гексана и получали белый порошок, выход 84%.Example 24
5-Chloro-2- (4-hydroxypiperidino) acetamido-N- (3,4-methylenedioxybenzyl) benzamide

5-Chloro-2-chlorocetamido-N- (3,4-methylenedioxybenzyl) benzamide (570 mg) was dissolved in 5 ml of N, N-dimethylformamide, 450 mg of 4-hydroxypiperidine, 620 mg of potassium carbonate and a catalytic amount of tetra- were added -butyl) ammonium iodide. The resulting mixture was stirred at room temperature for 1 hour, and then water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)) and recrystallized from ethyl acetate / n-hexane to give a white powder, yield 84%.

Mp 149-152 ^o C
(ethyl acetate / n-hexane).

Mass: (FAB) 446 (MH ⁺ ).

Elemental analysis:
calculated (%): C 59.26, H 5.43, N 9.42;
found (%): C 59.28, H 5.51, N 9.37.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.55 - 1.65 (m, 2H), 1.68 - 1.78 (m, 2H), 2.19 - 2.28 (m, 2H), 2.64 - 2.73 (m, 2H), 3.06 (s, 2H), 3.50 (m, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.58 (d, J = 3.7 Hz, 1H), 5.99 (s, 2H), 6.83 (dd, J = 1.3, 8.1 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 7.54 (dd, J = 2.6, 9.0 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 9.23 (t, J = 5.9 Hz, 1H), 11.69 (s, 1H).

Белый порошок получали с выходом 45%
Т.пл. 155-156^oC
(этилацетат/н-гексан).Example 25
5-Chloro-N- (3,4-methylenedioxybenzyl) -2- (piperidinoacetamido) - benzamide

White powder was obtained in 45% yield.
Mp 155-156 ^o C
(ethyl acetate / n-hexane).

Mass: (FAB) 430 (MH ⁺ ).

Elemental analysis (%):
calculated: C 61.47, H 5.63, N 9.77;
Found: C, 61.38; H, 5.61; N, 9.75.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.42 (m, 2H), 1.52 - 1.51 (m, 4H), 2.35 - 2.45 (m, 4H), 3.03 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H), 5.98 (s, 3H), 6.81 (dd, J = 1.3, 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 7.54 (dd, J = 2.6, 9.0 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 9.25 (t, J = 5.9 Hz, 1H), 11.70 (s, 1H).

Белое аморфное вещество получали с выходом 99%.Example 26
5-Chloro-2- [4- (ethoxycarbonyl) piperidino] acetamido-N- (3,4-methylenedioxybenzyl) benzamide

A white amorphous substance was obtained in 99% yield.

NMR (400 MHz, CDCl ₃ ) δ:
1.24 (t, J = 7.1 Hz, 3H), 1.90 - 1.98 (m, 2H), 1.98 2.10 (m, 2H), 2.26 - 2.36 (m, 3H), 2.81 - 2.90 (m, 2H), 3.10 (s , 2H), 4.13 (q, J = 7.1 Hz, 2H), 4.50 (d, J = 5.9 Hz, 2H), 5.96 (s, 2H), 6.71 (t, J = 5.9 Hz, 1H), 6.77 (dd , J = 0.4, 7.9 Hz, 1H), 6.81 (dd, J = 1.8, 7.9 Hz, 1H), 6.85 (dd, J = 0.4, 1.8 Hz, 1H), 7.30 (dd, J = 2.4, 9.0 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 11.61 (s, 1H).

Белый порошок получали с выходом 70%.Example 27
5-Chlorop-N- (3,4-methylenedioxybenzyl) -2 - [(4-methylpiperazino) - acetamido] benzamide

White powder was obtained in 70% yield.

Mp 162-164 ^o C
(EtOAc / n-Hex).

Mass: (FAB) 445 (MH ⁺ ).

Elemental analysis (%):
calculated: C 59.39, H 5.66, N 12.59;
Found: C, 58.80; H, 5.66; N, 12.45.

NMR (400 MHz, CDCl ₃ ) δ:
2.35 (s, 3H), 2.50 - 2.75 (m, 8H), 3.17 (s, 2H), 4.53 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.40 (w, 1H), 6.77 - 6.82 (m, 2H), 6.85 (m, 1H), 7.39 (dd, J = 2.0, 8.8 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 11.56 (w, 1H).

Белые хлопья получали с выходом 52%
Т.пл. 202-203^oC
(из водного этанола).Example 28
5-Chloro-N- (3,4-methylenedioxybenzyl) -2 - [(3-oxopiperazino) - acetamido] benzamide

White flakes were obtained with a yield of 52%
Mp 202-203 ^o C
(from aqueous ethanol).

Mass: (FAB) 445 (MH ⁺ ).

Elemental analysis (%):
calculated: C 56.70, H 4.76, N 12.59;
Found: C, 56.65; H, 4.78; N, 12.56.

NMR (400 MHz, DMSO-d ₆ ) δ:
2.65 (t, J = 5.3 Hz, 2H), 3.10 (s, 2H), 3.21 (s, 2H), 3.23 - 3.30 (m, 2H), 4.36 (d, J = 5.7 Hz, 2H), 5.99 (s , 2H), 6.81 (dd, J = 1.6, 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 7.56 (dd, J = 2.6, 9.0 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.83 (w s, 1H), 8.52 (d, J = 9.0 Hz, 1H), 9.26 (t, J - 5.7 Hz, 1H), 11.72 (s, 1H).

6-Хлор-1-[4-(этоксикарбонил)бутил] -1,2-дигидро-4H-1,3- бензоксазин-2,4-дион (3.50 г) растворяли в 35 мл диметилформамида и добавляли 0.13 г 4-диметиламинопиридина и 1.47 мл 3,4-метилендиоксибензиламина. Смесь перемешивали при комнатной температуре 1 ч и добавляли лед с водой. Образующуюся смесь экстрагировали этилацетатом. Органическую фазу промывали 1н. соляной кислотой, насыщенным водным раствором гидрокарбоната натрия и насыщенным водным раствором соли, последовательно, сушили над безводным сульфатом магния и растворитель отгоняли. Полученное твердое вещество промывали этанолом и получали 3.35 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 72%.Example 29
5-Chloro-2- [4- (ethoxycarbonyl) butylamino] -N- (3,4-methylenedioxybenzyl) benzamide

6-Chloro-1- [4- (ethoxycarbonyl) butyl] -1,2-dihydro-4H-1,3-benzoxazine-2,4-dione (3.50 g) was dissolved in 35 ml of dimethylformamide and 0.13 g of 4-dimethylaminopyridine was added and 1.47 ml of 3,4-methylenedioxybenzylamine. The mixture was stirred at room temperature for 1 hour and ice-water was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of salt were successively dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting solid was washed with ethanol to give 3.35 g of the title compound as a slightly yellow powder, yield 72%.

Mp 89-91 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
1.25 (t, J = 7.1 Hz, 3H), 1.65 - 1.80 (m, 4H), 2.35 (t, J = 7.0 Hz, 2H), 3.13 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H ), 4.46 (d, J = 5.7 Hz, 2H), 5.96 (s, 2H), 6.26 (br t, 1H), 6.60 (d, J = 9.0 Hz, 1H), 6.76 - 6.81 (m, 2H), 6.83 (m, 1H), 7.22 (dd, J = 2.4, 9.0 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.52 (br t, 1H).

Бледно-желтое твердое вещество получали с выходом 88%.Example 30
5-Chloro-2- [3- (ethoxycarbonyl) propylamino] -N- (3,4-methylenedioxybenzyl) benzamide

A pale yellow solid was obtained in 88% yield.

NMR (400 MHz, CDCl ₃ ) δ:
1.26 (t, J = 7.1 Hz, 3H), 1.97 (m, 2H), 2.42 (t, J = 7.3 Hz, 2H), 3.19 (m, 2H), 4.14 (k, J = 7.1 Hz, 2H), 4.47 (d, J = 5.5 Hz, 2H), 5.96 (s, 2H), 6.26 (m, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.76 - 6.82 (m, 2H), 6.83 (m, 1H), 7.22 (dd, J = 2.4, 8.8 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.57 (m, 1H).

Сероватый порошок получали с выходом 94%.Example 31
5-Chloro-2-methylamino-N- (3,4-methylenedioxybenzyl) benzamide

A grayish powder was obtained in 94% yield.

Mp 152-154 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, DMSO-d ₆ ) δ:
2.76 (d, J = 5.1 Hz, 3H), 4.31 (d, J = 5.9 Hz, 2H), 5.98 (s, 2H), 6.64 (d, J = 9.0 Hz, 1H), 6.73 (dd, J = 1.5 , 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 7.31 (dd, J = 2.6, 9.0 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.74 (q, J = 5.1 Hz, 1H), 8.93 (t, J = 5.9 Hz, 1H).

Слабо-желтый порошок получали с выходом 89%.Example 32
5-Chloro-2- (4-methoxycarbonylbenzylamino) -N- (3,4-methylenedioxybenzyl) benzamide

A slightly yellow powder was obtained in 89% yield.

Mp 156-158 ^o C
(white needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
3.91 (s, 3H), 4.46 (d, J = 5.5 Hz, 2H), 4.50 (d, J = 5.5 Hz, 2H), 5.97 (s, 2H), 6.29 (br, J = 5 Hz, 1H) , 6.46 (d, J = 9.0 Hz, 1H), 6.79 (dd, J = 0.7, 7.9 Hz, 1H), 6.82 (dd, J = 1.5, 7.9 Hz), 6.85 (dd, J = 0.7, 1.5 Hz) , 7.14 (dd, J = 2.6, 9.0 Hz), 7.31 (d, J = 2.6 Hz, 1H), 7.38 - 7.43 (m, 2H), 7.97 - 8.02 (m, 2H), 8.16 (w t, J = 5 Hz, 1H).

Суспензию 60% гидрида натрия в минеральном масле (1.34 г) суспендировали в 50 мл диметилформамида и добавляли по частям 3.0 г 6-хлор-1,2-дигидро-4H-1,3-бензоксазина. Полученную смесь перемешивали при комнатной температуре 1 ч и добавляли хлоргидрат 4- пиколилхлорида по частям. Через 1.5 ч образующуюся смесь нагревали до 50^oC, перемешивали 24 ч и оставляли охлаждаться. К смеси добавляли 3,4-метилендиоксибензиламин (2.1 мл) и 4-диметиламинопиридин (0.19 г). Полученную смесь перемешивали при комнатной температуре 1 ч и добавляли воду со льдом и смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и растворитель отгоняли. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (от 1:1 до 1:2)) и перекристаллизовывали из этанола и получали 870 мг указанного в заголовке соединения в виде белых игл, выход 14%.Example 33
5-Chloro-N- (3,4-methylenedioxybenzyl) -2- (4-picolyl) aminobenzamide

A suspension of 60% sodium hydride in mineral oil (1.34 g) was suspended in 50 ml of dimethylformamide and 3.0 g of 6-chloro-1,2-dihydro-4H-1,3-benzoxazine was added in portions. The resulting mixture was stirred at room temperature for 1 hour, and 4-picolyl chloride hydrochloride was added in portions. After 1.5 hours, the resulting mixture was heated to 50 ^° C, stirred for 24 hours and allowed to cool. To the mixture were added 3,4-methylenedioxybenzylamine (2.1 ml) and 4-dimethylaminopyridine (0.19 g). The resulting mixture was stirred at room temperature for 1 h and ice water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (1: 1 to 1: 2)) and recrystallized from ethanol to obtain 870 mg of the title compound as white needles, yield 14%.

Mp 163-166 ^o C.

Mass: (FAB) 396 (MH ⁺ ).

Elemental analysis (%):
calculated: C 63.72, H 4.58, N 10.62;
Found: C, 63.79; H, 4.57; N, 10.62.

NMR (400 MHz, CDCl ₃ ) δ:
4.43 (d, J = 5.9 Hz, 2H), 4.51 (d, J = 5.7 Hz, 2H), 5.97 (s, 2H), 6.40 (m, 1H), 6.40 (d, J = 9.0 Hz, 1H), 6.79 (dd, J = 0.5, 7.9 Hz, 1H), 6.82 (dd, J = 1.5, 7.9 Hz, 1H), 6.85 (dd, J = 0.5, 1.5 Hz, 1H), 7.15 (dd, J = 2.4, 9.0 Hz, 1H), 7.24 - 7.27 (m, 2H), 7.33 (d, J = 2.4 Hz, 1H), 8.21 (t, J = 5.9 Hz, 1H), 8.52 - 8.55 (m, 2H).

Бледно-желтый порошок получали с выходом 11%
Т.пл. 128-129^oC
(бледно-желтые иглы из водного EtOH).Example 34
5-Chloro-2 - [[trans-4- (ethoxycarbonyl) cyclohexyl] methylamino] - N- (3,4-methylenedioxybenzyl) benzamide

A pale yellow powder was obtained in 11% yield.
Mp 128-129 ^o C
(pale yellow needles from aqueous EtOH).

NMR (400 MHz, CDCl ₃ ) δ:
0.98 - 1.11 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.38 - 1.51 (m, 2H), 1.63 (m, 1H), 1.90 - 1.99 (m, 2H), 1.99 - 2.06 ( m, 2H), 2.25 (m, 1H), 2.95 - 3.02 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 4.48 (q, J = 5.7 Hz, 2H), 5.96 (s, 2H ), 6.21 (br t, 1H), 6.60 (d, J = 9.0 Hz, 1H), 6.76 - 6.82 (m, 2H), 6.83 (m, 1H), 7.21 (dd, J = 2.6, 9.0 Hz, 1H ), 7.26 (d, J = 2.6 Hz, 1H), 7.65 (br t, 1H).

2-Амино-5-хлор-N-(3,4-метилендиоксибензил)бензамид (1.0 г) растворяли в 10 мл пиридина и добавляли 0.41 г глутарового ангидрида. Смесь перемешивали при комнатной температуре 20 ч, концентрировали и добавляли этилацетат. Образующуюся смесь экстрагировали 1н. гидроксида натрия и устанавливали в водной фазе pH 2. Осадок отделяли фильтрованием, перекристаллизовывали из водного этанола и получали 500 мг указанного в заголовке соединения в виде белого порошка, выход 36%.Example 35
2 - [(4-Carboxybutyryl) amino] -5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide (1.0 g) was dissolved in 10 ml of pyridine and 0.41 g of glutaric anhydride was added. The mixture was stirred at room temperature for 20 hours, concentrated and ethyl acetate was added. The resulting mixture was extracted with 1N. sodium hydroxide and adjusted to pH 2 in the aqueous phase. The precipitate was filtered off and recrystallized from aqueous ethanol to give 500 mg of the title compound as a white powder, yield 36%.

Mp 154-155 ^o C (aqueous ethanol).

Mass: (FAB) 419 (MH ⁺ ).

Elemental analysis (%):
calculated: C 57.35, H 4.57, N 6.69;
Found: C 57.17, H 4.56, N 6.64.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.80 (dt, J = 7.3, 7.5 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 2.38 (t, 7.5 Hz, 2H), 4.37 (d, J = 5.9 Hz, 2H), 5.99 ( s, 2H), 6.82 (dd, J = 1.6, 7.9 Hz, 1H), 6.87 (dd, J = 0.4, 7.9 Hz, 1H), 6.93 (dd, J = 0.4, 1.6 Hz, 1H), 7.55 (dd , J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 9.30 (t, J = 5.9 Hz, 1H), 11.17 (s , 1H).

Белые иглы получали с выходом 38%.Example 36
2 - [(3-Carboxypropionyl) amino] -5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained in 38% yield.

Mp 217-220 ^o C (EtOH).

Mass: (FAB) 405 (MH ⁺ ).

Elemental analysis (%):
calculated: C 56.37, H 4.23, N 6.92;
Found: C, 56.24; H, 4.25; N, 6.88.

NMR (400 MHz, DMSO-d ₆ ) δ:
2.48 - 2.60 (m, 4H), 4.38 (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.82 (ddd, J = 0.4, 1.7, 7.9 Hz, 1H), 6.87 (dd, J = 1.7, 7.9 Hz, 1H), 6.93 (dd, J = 0.4, 1.7 Hz, 1H), 7.55 (dd, J = 2.4, 9.0 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.38 ( d, J = 9.0 Hz, 1H), 9.31 (t, J = 5.9 Hz, 1H), 11.24 (s, 1H).

Белое аморфное вещество получали с выходом 39%.Example 37
2- [N- (4-Carboxybutyryl) -N-methyl] amino-5-chloro-N '- (3,4-methylenedioxybenzyl) benzamide

A white amorphous substance was obtained in 39% yield.

Mass: (FAB) 433 (MH ⁺ ).

NMR (400 MHz, CDCl ₃ ) δ:
1.75 - 1.86 (m, 2H), 1.99 - 2.48 (m, 4H), 3.15, 3.22 (s, total 3H), 4.41 (dd, J = 5.7, 14.5 Hz, 1H), 4.46 (dd, J = 5.7, 14.5 Hz, 1H), 5.94 (s, 2H), 6.69, 7.04 (m, total 1H), 6.73 - 6.82 (m, 3H), 7.05, 7.12 (d, J = 8.4 Hz, total 1H), 7.40, 7.44 (dd, J = 2.4, 8.4 Hz, 1H), 7.47, 7.60 (d, J = 2.4 Hz, 1H).

Этанол (100 мл), тетрагидрофуран (100 мл) и 1н. гидроксид натрия (65 мл) добавляли к 10.09 г этил-1-[[4-хлор-2-[(3,4- метилендиоксибензил)карбамоил] фенил] карбамоил]пиперидин-4- карбоксилата. Смесь перемешивали при комнатной температуре 2 ч и добавляли 100 мл воды. Образующуюся смесь концентрировали и добавляли воду и этилацетат. Водную фазу отделяли, а органическую фазу экстрагировали 1н. гидроксида натрия. Обе водные фазы объединяли и устанавливали pH 2 концентрированной соляной кислоты. Осадок отделяли фильтрованием, перекристаллизовывали из водного этанола и получали 6.84 г указанного в заголовке соединения в виде белых игл, выход 72%.Example 38
1 - [[4-Chloro-2 - [(3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylic acid

Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N. sodium hydroxide (65 ml) was added to 10.09 g of ethyl 1 - [[4-chloro-2 - [(3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylate. The mixture was stirred at room temperature for 2 hours and 100 ml of water was added. The resulting mixture was concentrated and water and ethyl acetate were added. The aqueous phase was separated, and the organic phase was extracted with 1N. sodium hydroxide. Both aqueous phases were combined and the pH was adjusted to 2 with concentrated hydrochloric acid. The precipitate was separated by filtration, recrystallized from aqueous ethanol to obtain 6.84 g of the title compound as white needles, yield 72%.

Mp 263-264 ^o C (EtOH).

Mass: (FAB) 460 (MH ⁺ ).

Elemental analysis (%):
calculated: C 57.46, H 4.82, N 9.14;
Found: C, 57.39; H, 4.73; N, 9.09.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.46 (m, 2H), 1.86 (m, 2H), 2.49 (m, 1H), 2.98 (m, 2H), 3.91 (m, 2H), 4.38 (d, J = 5.7 Hz, 2H), 5.98 (s , 2H), 6.81 (dd, J = 1.5, 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 7.49 (dd, J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 9.35 (t, J = 5.7 Hz), 11.06 (s, 1H).

Этанол (100 мл), тетрагидрофуран (100 мл) и 1н. гидроксид натрия (65 мл) добавляли к 10.0 г 5-хлор-2-[транс-4-(этоксикарбонил)- циклогексанкарбонил] амино-N-(3,4-метилендиоксибензил)бензамида. Полученную смесь перемешивали при комнатной температуре 8 ч и концентрировали. Остаток растворяли в воде и подвергали хроматографии с обращенной фазой на силикагеле (растворитель: смесь вода/метанол, содержащая 30% воды). Фракции объединяли и концентрировали для удаления метанола. Образующийся раствор подкисляли 1н. соляной кислоты. Осадок отделяли фильтрованием, перекристаллизовывали из водного этанола и получали 7.10 г указанного в заголовке соединения в виде белых игл, выход 75%.Example 39
2- (trans-4-carboxycyclohexanecarbonylamino) -5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

Ethanol (100 ml), tetrahydrofuran (100 ml) and 1N. sodium hydroxide (65 ml) was added to 10.0 g of 5-chloro-2- [trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino-N- (3,4-methylenedioxybenzyl) benzamide. The resulting mixture was stirred at room temperature for 8 hours and concentrated. The residue was dissolved in water and subjected to reverse phase chromatography on silica gel (solvent: water / methanol mixture containing 30% water). Fractions were combined and concentrated to remove methanol. The resulting solution was acidified with 1N. of hydrochloric acid. The precipitate was separated by filtration, recrystallized from aqueous ethanol to obtain 7.10 g of the title compound as white needles, yield 75%.

Mp 228-230 ^o C (from ethanol).

Mass: (FAB) 459 (MH ⁺ ).

Elemental analysis (%):
calculated: C 60.20, H 5.05, N 6.10;
Found: C, 59.95; H, 5.11; N, 6.08.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.31 - 1.48 (m, 4H), 1.87 - 2.03 (m, 4H), 2.13 - 2.29 (m, 2H), 4.38 (d, J = 5.7 Hz, 2H), 5.99 (s, 2H), 6.82 (dd, J = 1.6, 7.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 2.6, 9.0 Hz, 1H), 7.83 ( d, J = 2.6 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 9.32 (t, J = 5.7 Hz, 1H), 11.19 (s, 1H).

Белые иглы получали с выходом 30%.Example 40
2- (5-Carboxyvaleryl) amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained in 30% yield.

Mp 197-199 ^o C (from ethanol).

Mass: (FAB) 433 (MH ⁺ ).

Elemental analysis (%):
calculated: C 58.27, H 4.89, N 6.47;
Found: C, 58.03; H, 4.96; N, 6.38.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.49 - 1.63 (m, 4H), 2.23 (t, J = 7.3 Hz, 2H), 2.34 (t, J = 6.8 Hz, 2H), 4.37 (d, J = 5.7 Hz, 2H), 5.99 (s, 2H ), 6.82 (dd, J = 1.6, 7.9 Hz, 1H), 6.87 (dd, J = 0.4, 7.9 Hz, 1H), 6.93 (dd, J = 0.4, 1.6 Hz, 1H), 7.55 (dd, J = 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 9.30 (t, J = 5.7 Hz, 1H), 11.15 (s, 1H) .

Белые иглы получали с выходом 74%.Example 41
2- (4-Carboxybenzoyl) amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained in 74% yield.

Mp 260-262 ^o C (from aqueous ethanol)
Mass: (FAB) 453 (MH ⁺ ).

Elemental analysis (%):
calculated: C 61.00, H 3.78, N 6.19;
Found: C, 60.83; H, 3.98; N, 6.09.

NMR (400 MHz, DMSO-d ₆ ) δ:
4.42 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.83 (dd, J = 1.5, 7.9 Hz, 1H), 6.86 (dd, J = 0.5, 7.9 Hz, 1H), 6.95 (dd , J = 0.5, 1.5 Hz, 1H), 7.66 (dd, J = 2.4, 9.0 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.98 8.03 (m, 2H), 8.09 - 8.15 (m , 2H), 8.62 (d, J = 9.0 Hz, 1H), 9.47 (t, J = 5.7 Hz, 1H), 12.50 (s, 1H).

Белые иглы получали с выходом 26%
Т.пл. 288-291^oC
(водный EtOH).Example 42
1 - [[4-Chloro-2 - [[(2,3-dihydrobenzofuran-5-yl) methyl] carbamoyl] - phenyl] carbamoyl] piperidine-4-carboxylic acid

White needles were obtained in 26% yield.
Mp 288-291 ^o C
(aqueous EtOH).

Mass: (FAB) 458 (MH ⁺ ).

Elemental analysis (%):
calculated: C 60.33, H 5.28, N 9.18;
Found: C, 60.18; H, 5.25; N, 9.16.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.47 (m, 2H), 1.86 (m, 2H), 2.47 (m, 1H), 2.99 (m, 2H), 3.15 (t, J = 8.8 Hz, 2H), 3.91 (m, 2H), 4.38 (d , J = 5.9 Hz, 2H), 4.50 (t, J = 8.8 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 1.8, 8.2 Hz, 1H), 7.20 (d , J = 1.8 Hz, 1H), 7.48 (dd, J = 2.6, 9.2 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 9.34 (t , J = 5.9 Hz, 1H), 11.12 (s, 1H).

Белые иглы получали с выходом 63%
Т.пл. 288-291^oC
(водный EtOH).Example 43
1 - [[4-Chloro-2- (3-chloro-4-methoxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylic acid

White needles were obtained in 63% yield.
Mp 288-291 ^o C
(aqueous EtOH).

Mass: (FAB) 480 (MH ⁺ ).

Elemental analysis (%):
calculated: C 55.01, H 4.83, N 8.75)
Found: C 54.80, H 4.81, N 8.64.

NMR (400 MHz, DMSO-d ₆ ) δ:
1.47 (m, 2H), 1.86 (m, 2H), 2.46 (m, 1H), 2.99 (m, 2H), 3.83 (s, 3H), 3.91 (m, 2H), 4.40 (d, J = 5.7 Hz , 2H), 7.11 (d, J = 9.6 Hz, 1H), 7.28 (dd, J = 2.0, 8.6 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.49 (dd, J 2.6, 9.0 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 9.37 (t, J = 5.7 Hz), 11.02 (s, 1H).

Белые иглы получали с выходом 9%
Т.пл. 256-258^oC (разл.)
(этанол).Example 44
2- (3-Carboxyacryloyl) amino-5-chloro-N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained in 9% yield
Mp 256-258 ^o C (decomp.)
(ethanol).

Mass: (FAB) 403 (MH ⁺ ).

Elemental analysis (%):
calculated: C 56.66, H 3.75, N 6.95;
Found: C, 56.17; H, 3.68; N, 6.75.

NMR (400 MHz, DMSO-d ₆ ) δ:
4.38 (d, J = 5.7 Hz, 2H), 5.98 (s, 2H), 6.64 (d, J = 15.4 Hz, 1H), 6.82 (dd, J = 1.5, 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 15.4 Hz, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 9.29 (t, J = 5.7 Hz, 1H), 11.49 (s, 1H).

Белые иглы получали с выходом 74%.Example 45
5-bromo-2- (trans-4-carboxycyclohexanecarbonyl) amino- N- (3,4-methylenedioxybenzyl) benzamide

White needles were obtained in 74% yield.

Mp 236-238 ^o C
(white needles from aqueous EtOH).

NMR (406 MHz, DMSO-d ₆ ) δ:
1.31 - 1.47 (m, 4H), 1.85 - 2.03 (m, 4H), 2.14 - 2.30 (m, 2H), 4.38 (d, J = 5.9 Hz, 2H), 5.99 (s, 2H), 6.81 (dd, J = 1.5, 7.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 2.4, 9.0 Hz, 1H), 7.94 ( d, J = 2.4 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 9.33 (t, J = 5.9 Hz, 1H), 11.20 (s, 1H), 12.09 (w, 1H).

Белые призмы получали с выходом 78%.Example 46
2- (trans-4-carboxycyclohexanecarbonyl) amino-5-chloro-N-methyl-N- (3,4-methylenedioxybenzyl) benzamide

White prisms were obtained in 78% yield.

Mp 202-204 ^o C
(white prisms from aqueous EtOH)
NMR (400 MHz, DMSO-d ₆ ) δ:
1.24 - 1.50 (m, 4H), 1.66 - 2.01 (m, 4H), 2.10 - 2.42 (m, 2H), 2.67, 2.83 (s, total 3H), 4.22, 4.51 (s, total 2H), 6.00, 6.01 (s, total 2H), 6.62 - 6.67, 6.80 - 6.89 (m, total 2H), 6.77, 7.02 (s, total 1H), 7.35 - 7.57 (m, 3H), 9.57, 9.62 (s, total 1H), 12.08 (w, 1H).

Этанол (7 мл), тетрагидрофуран (7 мл) и 1н. гидроксид натрия (7 мл) добавляли к 800 мг 5-хлор-2-[транс-4-(этоксикарбонил)- циклогексил]метил] амино-N-(3,4-метилендиоксибензил)бензамида и смесь перемешивали при комнатной температуре 17 ч.Example 47
sodium trans-4- [4-chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] aminomethylcyclohexanecarboxylate

Ethanol (7 ml), tetrahydrofuran (7 ml) and 1N. sodium hydroxide (7 ml) was added to 800 mg of 5-chloro-2- [trans-4- (ethoxycarbonyl) cyclohexyl] methyl] amino-N- (3,4-methylenedioxybenzyl) benzamide and the mixture was stirred at room temperature for 17 hours.

 The reaction mixture was concentrated and purified by silica gel column chromatography (solvent: 40% aqueous methanol). Fractions were combined and concentrated to dryness. The solid residue was washed with 2-propanol to obtain 780 mg of the title compound as a slightly yellow powder, yield 98%.

Mp 266-271 ^o C (decomp.).

Mass: (FAB) 489 (M + Na) ⁺ , 467 (MH ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
0.85 - 1.00 (m, 2H), 1.13 - 1.28 (m, 2H), 1.44 (m, 1H), 1.69 - 1.80 (m, 2H), 1.80 - 1.92 (m, 2H), 2.85 2.97 (m, 2H) , 4.32 (d, J = 5.5 Hz, 2H), 5.98 (s, 2H), 6.67 (d, J = 9.3 Hz, 1H), 6.78 (dd, J = 1.5, 7.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 7.26 (dd, J = 2.4, 9.3 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.97 (t, J = 5.5 Hz, 1H), 9.03 (t, J = 5.7 Hz, 1H).

Слабо-желтый порошок получали с выходом 88%
Т.пл. > 300^oC.Example 48
4 - [[4-Chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] - sodium aminomethylbenzoate

A slightly yellow powder was obtained in 88% yield.
Mp > 300 ^o C.

Mass: (FAB) 461 (MH ⁺ ), 483 ((M + Na) ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
4.33 (d, J = 5.7 Hz, 2H), 4.36 (d, J = 5.5 Hz, 2H), 5.99 (s, 2H), 6.63 (d, J = 9.0 Hz, 1H), 6.80 (dd, J = 1.5 , 7.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 2.6 , 8.1 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 8.29 (t, J = 5.7 Hz, 1H), 9.03 (t, J = 5.5 Hz, 1H).

Слабо-желтый порошок получали с выходом 35%.Example 49
4 - [[4-Chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] - sodium aminobutyrate

A slightly yellow powder was obtained in 35% yield.

Mass: (FAB) 435 (MH + Na ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
1.71 (m, 2H), 1.98 (m, 2H), 3.06 (m, 2H), 4.32 (d, J = 4.4 Hz, 2H), 5.98 (s, 2H), 6.72 (d, J = 9.0 Hz, 1H ), 6.79 (dd, J = 1.1, 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 1.1 Hz, 1H), 7.25 (dd, J = 2.4, 9.0 Hz , 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.86 (t, J = 4.4 Hz, 1H), 9.00 (d, J = 5.5 Hz).

Слабо-желтый порошок получали с выходом 41%.Example 50
5 - [[4-Chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] - sodium aminovalerate

A slightly yellow powder was obtained in 41% yield.

Mass: (FAB) 449 ((M + Na) ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
1.48 - 1.60 (m, 4H), 1.88 - 1.98 (m, 2H), 2.99 -3.08 (m, 2H), 4.32 (d, J = 5.3 Hz, 2H), 5.97 (s, 2H), 6.66 (d, J = 9.0 Hz, 1H), 6.79 (dd, J = 1.5, 7.9 Hz, 1H), 6.85 (d, J = 7.9 Hz), 6.89 (d, J = 1.5 Hz, 1H), 7.27 (dd, J = 2.4, 9.0 Hz), 7.67 (d, J = 2.4 Hz, 1H), 7.87 (t, J = 5.3 Hz, 1H), 9.04 (t, J = 5.3 Hz, 1H).

Белый порошок получали с выходом 76%
Т.пл. 244-249^oC (разл.).Example 51
1 - [[[4-Chloro-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoylmethyl] piperidine-4-carboxylate sodium

White powder was obtained in 76% yield.
Mp 244-249 ^o C (decomp.).

Mass: (FAB) 518 ((M + Na) ⁺ ), 496 (MH ⁺ ).

NMR (400 MHz, DMSO-d ₆ ) δ:
1.68 - 1.85 (m, 4H), 2.05 - 2.16 (m, 2H), 2.67 - 2.77 (m, 2H), 3.01 (s, 2H), 3.42 (w, 1H), 4.38 (w, s, 2H), 5.98 (s, 2H), 6.85 (dd, J = 1.3, 8.1 Hz, 1H), 6.87 (dd, J = 0.7, 8.1 Hz, 1H), 6.93 (d, J = 0.7 Hz, 1H), 7.52 (dd , J = 2.6, 9.0 Hz, 1H), 7.74 (d, J = 2.6 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 9.38 (w, 1H), 11.59 (w, 1H).

Белый порошок получали с выходом 48%.Example 52
4 - [[[4-Dimethylaminomethyl-2- (3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] sodium benzoate

White powder was obtained with a yield of 48%.

Mp 280 ^o C (decomp.).

NMR (400 MHz, DMSO-d ₆ ) δ:
2.16 (s, 6H), 3.38 (s, 2H), 4.33 (d, J = 4.9 Hz, 2H), 5.98 (s, 2H), 6.82 - 6.88 (m, 2H), 6.95 (s, 1H), 7.48 (dd, J = 0.5, 8.4 Hz, 1H), 7.92 (d, J = 0.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.1 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 9.45 (w, 1H), 12.42 (s, 1H).

2-Амино-5-бром-4-метоксибензойную кислоту (1.50 г), пиперониламин (0.84 мл), гидрохлорид 1-(3-диметиламинопропил)-3- этилкарбодиимида (1.29 г), 1-гидроксибензтриазол (0.91 г) и триэтиламин (0.93 мл) добавляли к 20 мл N, N-димeтилфopмaмида. Смесь перемешивали при комнатной температуре 20 ч и добавляли воду. Образовавшийся осадок отделяли фильтрованием и получали 2.19 г целевого соединения в виде слабо-оранжевого порошка, выход 100%.Example 53
2-amino-5-bromo-4-methoxy-N- (3,4-methylenedioxybenzyl) benzamide

2-amino-5-bromo-4-methoxybenzoic acid (1.50 g), piperonylamine (0.84 ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.29 g), 1-hydroxybenzotriazole (0.91 g) and triethylamine ( 0.93 ml) was added to 20 ml of N, N-dimethylformamide. The mixture was stirred at room temperature for 20 hours and water was added. The precipitate formed was filtered off and 2.19 g of the target compound was obtained in the form of a slightly orange powder, yield 100%.

 Mp 143-144.

Mass: 378 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.85 (3H, s), 4.46 (2H, d, J = 5.7 Hz), 5.81 (2H, s), 5.95 (2H, s), 6.15 (1H, s), 6.15 (1H, m), 6.77 (1H , dd, J = 7.9, 0.5 Hz), 6.79 (IH, dd, J = 7.9, 2.2 Hz), 6.83 (1H, dd, J = 2.2, 0.5 Hz), 7.44 (1H, s).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-оранжевого порошка, выход 100%.Example 54
2-amino-5-bromo-M- (3-chloro-4-methoxybenzyl) -4-methoxybenzamide

The title compound was obtained, as in Example 53, as a weak orange powder, yield 100%.

Mp 146-148 ^o C.

Mass: 400 (MH ⁺ ).

NMR (400 MHz, CDCl ₃ ) δ:
3.85 (3H, s), 3.89 (3H, s), 4.47 (2H, d, J = 5.7 Hz), 5.81 (2H, s), 6.15 (1H, s), 6.23 (1H, t, J = 5.7 Hz ), 6.89 (1H, d, J = 8.4 Hz), 7.19 (1H, dd, J = 8.4, 2.2 Hz), 7.34 (1H, d, J = 2.2 Hz), 7.45 (1H, s).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-охристого порошка, выход 93%.Example 55
2-amino-5-chloro-n- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a slightly ocher powder, yield 93%.

Mp 176-178 ^o C.

Mass: 324 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.50 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.28 (1H, s), 6.63 (1H, d, J = 8.8 Hz), 6.90 (1H, d , J = 8.4 Hz), 7.15 (1H, dd, J = 8.4, 2.4 Hz), 7.21 (1H, dd, J = 8.4, 2.2 Hz), 7.27 (1H, d, J = 2.4 Hz), 7.36 (1H , d, J = 2.2 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде белого порошка, выход 73%.Example 56
2-amino-5-chloro-N - [(2-methoxy-5-pyridyl) methyl] benzamide

The title compound was obtained, as in Example 53, as a white powder, yield 73%.

Mp 156-159 ^o C.

Mass: 292 (MH ⁺ ).

NMR (400 MHz, CDCl ₃ ) δ:
3.94 (3H, s), 4.52 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.22 (1H, s), 6.63 (1H, d, J = 8.8 Hz), 6.75 (1H, d , J = 8.4 Hz), 7.15 (1H, dd, J = 8.8, 2.4 Hz), 7.25 (1H, dd, J = 2.4 Hz), 7.60 (1H, dd, J = 8.4, 2.6 Hz), 8.14 (1H , d, J = 2.6 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-желтого порошка, выход 100%.Example 57
2-amino-N- (3,4-methylenedioxybenzyl) -5-trifluoromethoxybenzamide

The title compound was obtained, as in Example 53, as a slightly yellow powder, yield 100%.

Mp 150-153 ^o C.

Mass: 354 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.50 (2H, d, J = 5.7 Hz), 5.59 (2H, s), 5.96 (2H, s), 6.19 (1H, s), 6.66 (1H, d, J = 8.8 Hz), 6.78 (1H, dd , J = 7.9, 0.5 Hz), 6.81 (1H, dd, J = 7.9, 1.5 Hz), 6.85 (1H, dd, J = 1.5, 0.5 Hz), 7.09 (1H, m), 7.14 (1H, d, J = 2.6 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде белого порошка, выход 100%.Example 58
2-amino-5-chlorop-n- (3-cyano-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a white powder, yield 100%.

Mp 174-177 ^o C
Mass: 315 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.89 (3H, s), 4.36 (2H, d, J = 5.7 Hz), 6.59 (2H, s), 6.73 (1H, d, J = 8.8 Hz), 7.17 (1H, dd, J = 8.8, 2.6 Hz ), 7.22 (1H, d, J = 8.6 Hz), 7.58-7.66 (3H, m), 8.89 (1H, t, J = 5.7 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-оранжевого порошка, выход 98%.Example 59
2-amino-5-bromo-N- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a weak orange powder, yield 98%.

Mp 168-170 ^o C.

Mass: 370 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.49 (2H, d, J = 5.7 Hz), 5.56 (2H, s), 6.30 (1H, s), 6.58 (1H, d, J = 8.8 Hz), 6.90 (1H, d , J = 8.4 Hz), 7.20 (1H, dd, J = 8.4, 2.2 Hz), 7.27 (1H, dd, J = 8.8, 2.2 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.40 (1H , d, J = 2.2 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-охристого порошка, выход 99%.Example 60
2-amino-5-chlorop-n- (4-chlorop-3-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a slightly buffy powder, yield 99%.

Mp 162-163 ^o C.

Mass: 324 (M ⁺ ).

H-NMR (400 MHz, CDCl ₃ δ:
3.91 (3H, s), 4.55 (2H, d, J = 5.7 Hz), 5.54 (2H, s), 6.31 (1H, s), 6.46 (1H, d, J = 8.8 Hz), 6.87 (1H, dd , J = 8.1, 1.8 Hz), 6.92 (1H, d, J = 1.8 Hz), 7.16 (1H, dd, J = 8.8, 2.4 Hz), 7.28 (1H, d, J = 2.4 Hz), 7.34 (1H , d, J = 8.1 Hz).

Указанное в заголовке соединение получали, как в примере 1, в виде слабо-желтого порошка, выход 88%.Example 61
2-amino-5-cyano-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 1, as a slightly yellow powder, 88% yield.

Mp 163-166 ^o C.

Mass: 295 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.49 (2H, d, J = 5.5 Hz), 5.96 (2H, s), 6.22 (1H, s), 6.40 (1H, m), 6.63 (1H, d, J = 8.6 Hz), 6.79 (1H, d , J = 8.1 Hz), 6.81 (1H, dd, J = 8.1, 1.3 Hz), 6.84 (1H, d, J = 1.3 Hz), 7.40 (1H, dd, J = 8.1, 1.8 Hz), 7.65 (1H , d, J = 1.8 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде бледно-желтого порошка, выход 100%.Example 62
2-amino-N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

The title compound was obtained, as in Example 53, as a pale yellow powder, yield 100%.

Mp 184-186 ^o C.

Mass: 316 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.50 (2H, d, J = 5.7 Hz), 6.23 (2H, s), 6.47 (1H, m), 6.67 (1H, d, J = 8.6 Hz), 6.92 (1H, d , J = 8.4 Hz), 7.22 (1H, dd, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.41 (1H, dd, J = 8.6, 2.0 Hz), 7.67 (1H , d, J = 2.0 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде желтого порошка, выход 79%.Example 63
2-amino-N- (3-chloro-4-methoxybenzyl) -5-nitrobenzamide

The title compound was obtained, as in Example 53, as a yellow powder, yield 79%.

Mp 194-198 ^o C.

Mass: 336 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.50 - 6.64 (3H, m), 6.66 (1H, d, J = 9.2 Hz), 6.91 (1H, d, J = 8.4 Hz ), 7.23 (1H, dd, J = 8.4, 2.2 Hz), 7.38 (1H, d, J = 2.6 Hz), 8.08 (1H, dd, J = 9.2, 2.6 Hz), 8.34 (1H, d, J = 2.4 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-желтого порошка, выход 93%.Example 64
2-amino-5-dimethylsulfamoyl-N-3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a slightly yellow powder, yield 93%.

Mp 195-199 ^o C.

Mass: 398 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.66 (6H, s), 3.89 (3H, s), 4.51 (2H, d, J = 5.9 Hz), 6.26 (2H, s), 6.72 (1H, d, J = 8.8 Hz), 6.89 (1H, d , J = 8.4 Hz), 6.89 (1H, t, J = 5.9 Hz), 7.24 (1H, dd, J = 8.4, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.54 (1H, dd , J = 8.8, 2.0 Hz), 7.84 (1H, d, J = 2.0 Hz).

Указанное в заголовке соединение получали, как в Примере 53, в виде слабо-желтого порошка, выход 78%.Example 65
2-amino-5-methylsulfamoyl-n- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 53, as a slightly yellow powder, 78% yield.

Mp 154-155 ^o C.

Mass: 383 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.57 (3H, d, J = 5.5 Hz), 3.87 (3H, s), 4.47 (2H, d, J = 5.9 Hz), 4.66 (1H, q, J = 5.5 Hz), 6.26 (2H, s), 6.68 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 8.6 Hz), 7.01 (1H, t, J = 5.9 Hz), 7.20 (1H, dd, J = 8.6, 2.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.57 (1H, dd, J = 8.6, 2.2 Hz), 7.93 (1H, d, J = 2.2 Hz).

N-(3,4-Метилендиоксибензил)-2-нитро-5-(1-пиразолил)бензамид (1.80 г) растворяли в 120 мл тетрагидрофурана и добавляли 1.8 г 10% палладия на угле (водосодержащего). Смесь подвергали каталитическому восстановлению при комнатной температуре и 1 атм. Через 13 ч катализатор отфильтровывали и реакционную смесь концентрировали в вакууме. Остаток кристаллизовали из эфира. Образующиеся кристаллы отделяли фильтрованием и получали 1.50 г целевого соединения в виде порошка, выход 91%.Example 66
2-amino-N- (3,4-methylenedioxybenzyl) -5- (1-pyrazolyl) benzamide

N- (3,4-Methylenedioxybenzyl) -2-nitro-5- (1-pyrazolyl) benzamide (1.80 g) was dissolved in 120 ml of tetrahydrofuran and 1.8 g of 10% palladium on carbon (water-containing) was added. The mixture was catalytically reduced at room temperature and 1 atm. After 13 hours, the catalyst was filtered off and the reaction mixture was concentrated in vacuo. The residue was crystallized from ether. The resulting crystals were separated by filtration and received 1.50 g of the target compound in powder form, yield 91%.

Mp 146-147 ^o C.

Mass: 336 (M ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.50 (2H, d, J = 5.7 Hz), 5.65 (2H, s), 5.95 (2H, s), 6.42 (1H, dd, J = 2.4, 1.8 Hz), 6.75 (1H, d, J = 8.8 Hz ), 6.77 (1H, d, J = 8.2 Hz), 6.81 (1H, dd, J = 8.2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.41 (1H, dd, J = 8.8, 2.4 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 2.4 Hz), 7.76 (1H, d, J = 2.4 Hz).

Указанное в заголовке соединение получали, как в Примере 66, в виде белого порошка, выход 94%.Example 67
2-amino-N- (3,4-methylenedioxybenzyl) -5- (1,2,4-triazol-1-yl) benzamide

The title compound was obtained, as in Example 66, as a white powder, yield 94%.

Mp 163-164 ^o C.

Mass: 338 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.51 (2H, d, J = 5.5 Hz), 5.79 (2H, s), 5.96 (2H, s), 6.48 (1H, s), 6.78 (1H, d, J = 8.2 Hz), 6.78 (1H, d , J = 8.9 Hz), 6.81 (1H, dd, J = 8.2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.41 (1H, dd, J = 8.9, 2.4 Hz), 7.62 (1H d, J = 2.4 Hz), 8.03 (1H, s), 8.37 (1H, s).

2-Амино-5-бром-4-метокси-N-(3-хлор-4-метоксибензил)бензамид (4.67 г) растворяли в 10 мл N-мeтил-2-пиppoлидoнa и добавляли 1.15 г цианида меди. Смесь перемешивали при 180^oC 4 ч и добавляли водный раствор этилендиамина. Полученную смесь экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3:2)). Полученное твердое вещество промывали эфиром и получали 1.58 г указанного в заголовке соединения в виде слабо-желтого порошка, выход 39%.Example 68
2-amino-4-methoxy-n- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

2-amino-5-bromo-4-methoxy-N- (3-chloro-4-methoxybenzyl) benzamide (4.67 g) was dissolved in 10 ml of N-methyl-2-pyrrolidone and 1.15 g of copper cyanide was added. The mixture was stirred at 180 ^° C. for 4 hours and an aqueous solution of ethylenediamine was added. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 2)). The resulting solid was washed with ether to give 1.58 g of the title compound as a slightly yellow powder, yield 39%.

Mp 184-185 ^o C.

Mass: 346 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.83 (3H, s), 3.90 (3H, s), 4.48 (2H, d, J = 5.9 Hz), 6.08 (1H, s), 6.32 - 6.42 (3H, m), 6.91 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 8.4, 2.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.59 (1H, s).

7-Амино-4-бромизоиндолинон (0.35 г) суспендировали в 50 мл диметилформамида и добавляли 0.29 г 60% гидрида натрия. Смесь перемешивали при комнатной температуре 45 мин и добавляли 0.29 г пиперонилхлорида. Полученную смесь перемешивали при комнатной температуре 4 ч и добавляли лед с водой и смесь экстрагировали этилацетатом. Органическую фазу промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3:1)). Твердый остаток промывали н-гексаном и получали 0.25 г указанного в заголовке соединения в виде бледно-желтого порошка, выход 46%.Example 69
7-amino-4-bromo-N- (3,4-methylenedioxybenzyl) isoindolin-1-one

7-amino-4-bromoisoindolinone (0.35 g) was suspended in 50 ml of dimethylformamide and 0.29 g of 60% sodium hydride was added. The mixture was stirred at room temperature for 45 minutes and 0.29 g of piperonyl chloride was added. The resulting mixture was stirred at room temperature for 4 hours and ice-water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of salt, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)). The solid residue was washed with n-hexane and 0.25 g of the title compound was obtained as a pale yellow powder, yield 46%.

Mp 151-153 ^o C.

Mass: 361 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.08 (2H, s), 4.63 (2H, s), 5.26 (2H, s), 5.95 (2H, s), 6.50 (1H, d, J = 8.6 Hz), 6.76 - 6.79 (3H, m), 7.28 (1H, d, J = 8.6 Hz).

Указанное в заголовке соединение получали, как в Примере 69, в виде слабо-желтого порошка, выход 84%.Example 70
8-amino-5-chloro-N- (3,4-methylenedioxybenzyl) -1,2,3,4-tetrahydroisoquinolin-1-one

The title compound was obtained, as in Example 69, as a slightly yellow powder, yield 84%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
2.94 (2H, t, J = 6.6 Hz), 3.40 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 5.94 (2H, s), 6.18 (2H, s), 6.46 (1H, d , J = 8.8 Hz), 6.75 (1H, dd, J = 7.9, 0.5 Hz), 6.78 (1H, dd, J = 7.9, 1.2 Hz), 6.82 (1H, dd, J = 1.2, 0.7 Hz), 7.30 (1H, d, J = 8.8 Hz).

1-(2-Карбокси-4-хлорфенилкарбамоил)-4-гидроксипиперидин (0.5 г), пиперониламин (0.42 мл), 1,3-дициклогексилкарбодиимид (0.38 г), 1-гидроксибензтриазол (0.25 г) и 4-диметиламинопиридин (25 мг) добавляли к 8 мл N.N-диметилформамида. Смесь перемешивали при комнатной температуре 61 ч и добавляли воду и этилацетат. Нерастворимый материал отфильтровывали, органическую фазу отделяли, промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: дихлорметан/метанол (30:1)). Полученное вещество кристаллизовали из н-гексан/этилацетата, перекристаллизовывали из водного этанола и получали 0.39 г целевого соединения в виде белого порошка, выход 53%.Example 71
1 - [[4-Chloro-2 - [(3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] -4-hydroxypiperidine

1- (2-Carboxy-4-chlorophenylcarbamoyl) -4-hydroxypiperidine (0.5 g), piperonylamine (0.42 ml), 1,3-dicyclohexylcarbodiimide (0.38 g), 1-hydroxybenzotriazole (0.25 g) and 4-dimethylaminopyridine (25 mg ) was added to 8 ml of NN-dimethylformamide. The mixture was stirred at room temperature for 61 hours and water and ethyl acetate were added. Insoluble material was filtered off, the organic phase was separated, washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of salt, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: dichloromethane / methanol (30: 1)). The resulting substance was crystallized from n-hexane / ethyl acetate, recrystallized from aqueous ethanol, and 0.39 g of the target compound was obtained in the form of a white powder, yield 53%.

Mp 151-155 ^o C (decomp.).

Mass: 432 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
0.56 (2H, m), 1.74 (1H, m), 1.95 (2H, m), 3.21 (2H, ddd, J = 13.6, 9.3, 3.3 Hz), 3.83 - 3.97 (3H, m), 4.47 (2H, d, J = 5.7 Hz), 5.96 (2H, s), 6.87 (1H, dd, J = 7.9, 0.5 Hz), 6.81 (1H, dd, J = 7.9, 1.6 Hz), 6.85 (1H, dd, J = 1.6, 0.5 Hz), 7.03 (1H, t, J = 5.7 Hz), 7.25 (1H, dd, J = 9.2, 2.4 Hz), 7.33 (1H, d, J = 2.4 Hz), 8.21 (1H, d , J = 9.2 Hz), 10.57 (1H, s).

Этил-1-[(4-бром-2-карбоксифенил)карбамоил] пиперидин-4- карбоксилат (1.2 г), пиперониламин (0.56 мл), 1,3-дициклогексилкарбодиимид (0.68 г), 1-гидроксибензтриазол (0.45 г) и 4-диметиламинопиридин (каталитическое количество) добавляли к 10 мл диметилформамида. Полученную смесь перемешивали при комнатной температуре 20 ч, затем добавляли воду и этилацетат. Нерастворимый материал отфильтровывали, органическую фазу отделяли, промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Полученный остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (2:1)). Полученное твердое вещество промывали эфиром и получали 1.27 г указанного в заголовке соединения в виде белого порошка, выход 77%.Example 72
Ethyl 1 - [[4-bromo-2 - [(3,4-methylenedioxybenzyl) carbamoyl] phenyl] - carbamoyl] piperidine-4-carboxylate

Ethyl 1 - [(4-bromo-2-carboxyphenyl) carbamoyl] piperidine-4-carboxylate (1.2 g), piperonylamine (0.56 ml), 1,3-dicyclohexylcarbodiimide (0.68 g), 1-hydroxybenzotriazole (0.45 g) and 4-dimethylaminopyridine (catalytic amount) was added to 10 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 20 hours, then water and ethyl acetate were added. Insoluble material was filtered off, the organic phase was separated, washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of salt, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (2: 1)). The resulting solid was washed with ether to give 1.27 g of the title compound as a white powder, yield 77%.

Mp 156-159 ^o C.

Mass: 532 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 1.99 (2H, m), 2.52 (1H, m), 3.05 (2H, m), 4.09 (2H, m), 4.16 (2H , kV, J = 7.1 Hz), 4.47 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.79 (1H, dd, J = 8.1, 0.5 Hz), 6.82 (1H, dd, J = 8.1, 1.5 Hz), 6.85 (1H, dd, J = 1.5, 0.5 Hz), 6.89 (1H, t, J = 5.7 Hz), 7.39 (1H, dd, J = 9.0, 2.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 8.19 (1H, d, J = 9.0 Hz), 10.57 (1H, s).

1-[(2-Карбокси-4-хлорфенил)карбамоил] -4-гидроксипиперидин (0.5 г), 3-хлор-4-метоксибензиламинхлоргидрат (0.7 г), 1,3-дициклогексилкарбодиимид (0.38 г), 1-гидроксибензтриазол (0.25 г), 4-диметиламинопиридин (25 мг) и триэтиламин (0.47 мл) добавляли к 8 мл N,N-димeтилфopмaмидa. Полученную смесь перемешивали при комнатной температуре 61 ч и добавляли воду и этилацетат. Нерастворимый материал отфильтровывали, органическую фазу отделяли и промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и водным насыщенным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель дихлорметан/метанол (30: 1)). Полученное вещество кристаллизовали из н-гексана/этилацетата и перекристаллизовывали из водного этанола и получали 0.51 г указанного в заголовке соединения в виде белого порошка, выход 66%.Example 73
1 - [[4-Chloro-2 - [(3-chloro-4-methoxybenzyl) carbamoyl] phenyl] carbamoyl] - 4-hydroxypiperidine

1 - [(2-Carboxy-4-chlorophenyl) carbamoyl] -4-hydroxypiperidine (0.5 g), 3-chloro-4-methoxybenzylamine hydrochloride (0.7 g), 1,3-dicyclohexylcarbodiimide (0.38 g), 1-hydroxybenzotriazole (0.25 d) 4-dimethylaminopyridine (25 mg) and triethylamine (0.47 ml) were added to 8 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 61 hours, and water and ethyl acetate were added. Insoluble material was filtered off, the organic phase was separated and washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate, water and an aqueous saturated salt solution, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol solvent (30: 1)). The resulting material was crystallized from n-hexane / ethyl acetate and recrystallized from aqueous ethanol to give 0.51 g of the title compound as a white powder, yield 66%.

Mp 173-174 ^o C (decomp.).

Mass: 452 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.33 (2H, m), 1.76 (2H, m), 3.11 (2H, ddd, J = 13.0, 9.5, 3.1 Hz), 3.64 - 3.78 (3H, m), 3.84 (3H, s), 4.40 (2H, d, J = 5.7 Hz), 4.46 (1H, d, J = 4.2 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.28 (2H, dd, J = 8.6, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.50 (1H, dd, J = 9.2, 2.6 Hz), 7.82 (1H, d, J = 2.6 Hz), 8.32 (1H, d, J = 9.2 Hz), 9.37 (1H, t, J = 5.7 Hz), 11.02 (1H, s).

Указанное в заголовке соединение получали, как в Примере 73, в виде белого порошка, выход 13%.Example 74
1 - [[2 - [(3-Chloro-4-methoxybenzyl) carbamoyl] -4-cyanophenyl] carbamoyl] -4-hydroxypiperidine

The title compound was obtained, as in Example 73, as a white powder, yield 13%.

Mp 194-196 ^o C.

Mass: 443 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.35 (2H, m), 1.77 (2H, m), 3.16 (2H, m), 3.64 -3.80 (3H, m), 3.84 (3H, s), 4.42 (2H, d, J = 5.5 Hz), 4.77 (1H, d, J = 4.2 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.9, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.86 (1H, dd, J = 9.0, 1.6 Hz), 8.24 (1H, d, J = 1.6 Hz), 8.49 (1H, d, J = 9.0 Hz), 9.42 (1H, m), 11.47 (1H, s) .

Этил- 1-[(4-бром-2-карбоксифенил)карбамоил]пиперидин-4- карбоксилат (1.0 г), 3-хлор-4-метоксибензиламин (0.78 г), 1,3-дициклогексилкарбодиимид (0.57 г), 1-гидроксибензтриазол (0.37 г), 4-диметиламинопиридин (каталитическое количество) и триэтиламин (0.52 мл) добавляли к 8 мл диметилформамида. Полученную смесь перемешивали при комнатной температуре 66 ч и добавляли воду и этилацетат. Нерастворимый материал отфильтровывали, органическую фазу отделяли и промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрокарбоната натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (2: 1)). Твердое вещество промывали эфиром и получали 1.00 г указанного в заголовке соединения в виде белого порошка, выход 72%.Example 75
Ethyl 1 - [[4-bromo-2 - [(3-chloro-4-methoxybenzyl) carbamoyl] phenyl] - carbamoyl] piperidine-4-carboxylate

Ethyl 1 - [(4-bromo-2-carboxyphenyl) carbamoyl] piperidine-4-carboxylate (1.0 g), 3-chloro-4-methoxybenzylamine (0.78 g), 1,3-dicyclohexylcarbodiimide (0.57 g), 1- hydroxybenzotriazole (0.37 g), 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.52 ml) were added to 8 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 66 hours, and water and ethyl acetate were added. Insoluble material was filtered off, the organic phase was separated and washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of salt, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (2: 1)). The solid was washed with ether to give 1.00 g of the title compound as a white powder, yield 72%.

Mp 172-174 ^o C.

Mass: 554 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.75 (2H, m), 1.99 (2H, m), 2.52 (1H, m), 3.05 (2H, m), 3.91 (3H, s), 4.08 (2H , m), 4.16 (2H, q, J = 7.1 Hz), 4.47 (2H, d, J = 5.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.22 (1H, m), 7.22 (1H , dd, J = 8.4, 2.2 Hz), 7.33 (1H, dd, J = 9.2, 2.4 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.45 (1H, d, J = 2.4 Hz), 8.10 (1H, d, J = 9.2 Hz), 10.53 (1H, s).

5-Хлор-2-хлорацетамидо-N-(3-хлор-4-метоксибензил)бензамид (0.7 г), пиперидин (0.51 мл), безводный карбонат калия (0.72 г) и тетра-н-бутиламмонийиодид (каталитическое количество) добавляли к 6 мл диметилформамида. Полученную смесь перемешивали при комнатной температуре 1.5 ч, добавляли воду и экстрагировали этилацетатом. Органическую фазу промывали водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (3:1)), перекристаллизовывали из водного этанола и получали 0.37 г указанного в заголовке соединения в виде белых игл, выход 48%.Example 76
5-Chloro-N- (3-chloro-4-methoxybenzyl) -2- (piperidinoacetamido) benzamide

5-Chloro-2-chloroacetamido-N- (3-chloro-4-methoxybenzyl) benzamide (0.7 g), piperidine (0.51 ml), anhydrous potassium carbonate (0.72 g) and tetra-n-butylammonium iodide (catalytic amount) were added to 6 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 1.5 h, water was added and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (3: 1)), recrystallized from aqueous ethanol, and 0.37 g of the title compound was obtained as white needles, yield 48%.

Mp 126-129 ^o C.

Mass: 450 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.42 - 1.50 (2H, m), 1.66 - 1.74 (4H, m), 2.46 - 2.56 (4H, m), 3.07 (2H, s), 3.90 (3H, s), 4.53 (2H, d, J = 5.7 Hz), 6.62 (1H, t, J = 5.9 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 8.4, 2.2 Hz), 7.32 (1H, dd, J = 9.0 , 2.0 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.40 (1H, d, J = 2.4 Hz), 8.49 (1H, d, J = 9.0 Hz), 11.52 (1H, s).

Указанное в заголовке соединение получали, как в Примере 24, в виде слабо-желтых призм, выход 86%.Example 77
5-Chloro-N- (3-chloro-4-methoxybenzyl) -2- (pyrrolidinoacetamido) - benzamide

The title compound was obtained, as in Example 24, as weak yellow prisms, yield 86%.

Mp 98-100 ^o C.

Mass: 436 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.81 - 1.92 (4H, m), 2.61 - 2.72 (4H, m), 3.28 (2H, s), 3.89 (3H, s), 4.49 (2H, d, J = 5.9 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.89 (1H, t, J = 5.9 Hz), 7.19 (1H, dd, J = 8.4, 2.2 Hz), 7.27 (1H, dd, J = 9.0, 2.4 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.41 (1H, d, J = 2.4 Hz), 8.42 (1H, d, J = 9.0 Hz), 11.49 (1H, s).

Указанное в заголовке соединение получали, как в Примере 24, в виде бледно-желтых игл, выход 60%.Example 78
5-Chloro-N- (3,4-methylenedioxybenzyl) -2- (piperidinopropionylamido) benzamide

The title compound was obtained, as in Example 24, as pale yellow needles, yield 60%.

Mp 136-141 ^o C.

Mass: 444 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.40 - 1.48 (2H, m), 1.56 - 1.64 (4H, m), 2.44 (4H, s), 2.56 (2H, t, J = 7.0 Hz), 2.70 (2H, t, J = 7.0 Hz), 4.48 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.26 (1H, m), 6.78 (1H, d, J = 7.8 Hz), 6.80 (1H, d, J = 7.8 Hz), 6.83 (1H, s), 7.35 (1H, dd, J = 9.0, 2.4 Hz), 7.40 (1H, d, J = 2.4 Hz), 8.31 (1H, d, J = 9.0 Hz), 11.03 (1H, s) .

Указанное в заголовке соединение получали, как в Примере 24, в виде бледно-желтых игл, выход 7%.Example 79
5-Chloro-N- (3,4-methylenedioxybenzyl) -2- (4-piperidinobutyrylamino) - benzamide

The title compound was obtained, as in Example 24, as pale yellow needles, yield 7%.

Mp 121-122 ^o C.

Mass: 458 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.37 - 1.45 (2H, m), 1.51 - 1.59 (4H, m), 1.91 (2H, quintet, J = 7.5 Hz), 2.31 - 2.46 (8H, m), 4.50 (2H, d, J = 5.7 Hz) , 5.98 (2H, s), 6.43 (1H, m), 6.78 - 6.85 (3H, m), 7.39 (1H, d, J = 2.6 Hz), 7.39 (1H, dd, J = 9.7, 2.6 Hz), 8.56 (1H, d, J = 9.7 Hz), 10.96 (1H, s).

2-Амино-N-(3-хлор-4-метоксибензил)-5-цианобензамид (0.33 г) растворяли в 5 мл пиридина и охлаждали льдом. К раствору добавляли хлоргидрат изоникотиноилхлорида (0.2 г) и смесь перемешивали при комнатной температуре 4 ч и добавляли воду. Образующийся осадок отделяли фильтрованием, промывали водой и эфиром, перекристаллизовывали из этилацетата и получали бледно-желтые иглы, выход 64%.Example 80
5-cyano-2- (isonicotinoylamino) -N- (3-chloro-4-methoxybenzyl) benzamide

2-amino-N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide (0.33 g) was dissolved in 5 ml of pyridine and cooled with ice. Isonicotinoyl chloride hydrochloride (0.2 g) was added to the solution, and the mixture was stirred at room temperature for 4 h and water was added. The precipitate formed was filtered off, washed with water and ether, recrystallized from ethyl acetate, and pale yellow needles were obtained, yield 64%.

Mp 243-245 ^o C (decomp.).

Mass: 421 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.83 (2H, s), 4.47 (2H, d, J = 5.7 Hz), 7.32 (1H, dd, J = 8.4, 2.2 Hz), 7.46 (1H, d, J = 2.2 Hz), 7.79 - 7.83 (2H , m), 8.06 (1H, dd, J = 8.8, 1.8 Hz), 8.40 (1H, d, J = 1.8 Hz), 8.77 (1H, d, J = 8.8 Hz), 8.84 - 8.88 ( 2H, m), 9.56 (1H, t, J = 5.7 Hz), 12.90 (1H, s).

Указанное в заголовке соединение получали, как в Примере 80, в виде белых игл, выход 75%.Example 81
5-Bromo-N- (3-chloro-4-methoxybenzyl) -2- (isonicotinoylamino) benzamide

The title compound was obtained, as in Example 80, as white needles, yield 75%.

Mp 190-192 ^o C.

Mass: 476 (MH ⁺ ).

Указанное в заголовке соединение получали, как в Примере 80, в виде белых игл, выход 40%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.90 (3H, s), 4.57 (2H, d, J = 5.7 Hz), 6.70 (1H, t, J = 5.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.64 (1H, dd , J = 9.3, 2.2 Hz), 7.65 (1H, d, J = 2.2 Hz), 7.83 - 7.87 (2H, m), 8.72 (1H, d, J = 9.3 Hz), 8.81 - 8.85 (2H, m), 12.33 (1H, s)
Example 82
5-Bromo-2- (isonicotinoylamino) -4-methoxy-N- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 80, as white needles, yield 40%.

Mp 252-253 ^o C (decomp.).

Mass: 506 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.83 (3H, s), 3.95 (3H, s), 4.45 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.30 (1H, dd, J = 8.6, 2.2 Hz ), 7.42 (1H, d, J = 2.2 Hz), 7.80 - 7.84 (2H, m), 8.24 (1H, s), 8.55 (1H, s), 8.84 - 8.88 (2H, m), 9.39 (1H, t, J = 5.7 Hz), 13.26 (1H, s).

Указанное в заголовке соединение получали, как в Примере 80, в виде белых игл, выход 81%.Example 83
2- (Isonicotinoylamino) -4-methoxy-N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

The title compound was obtained, as in Example 80, as white needles, yield 81%.

Mp 262-267 ^o C (decomp.).

Mass: 451 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.83 (3H, s), 4.00 (3H, s), 4.46 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 8.6, 2.2 Hz ), 7.44 (1H, d, J = 2.2 Hz), 7.81 - 7.84 (2H, m), 8.40 (1H, s), 8.60 (1H, s), 8.85 - 8.90 (2H, m), 9.42 (1H, t, J = 5.7 Hz), 13.48 (1H, s).

Указанное в заголовке соединение получали, как в Примере 80, в виде бледно-желтых игл, выход 75%.Example 84
5-bromo-2- (isonicotinoylamino) -4-methoxy-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 80, as pale yellow needles, yield 75%.

Mp 249-254 ^o C (decomp.).

Mass: 484 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.94 (3H, s), 4.42 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.83 (1H, dd, J = 8.0, 1.3 Hz), 6.86 (1H, dd, J = 8.0, 0.4 Hz), 6.94 (1H, dd, J = 1.3, 0.4 Hz), 7.80 - 7.84 (2H, m), 8.24 (1H, s), 8.55 (1H, s), 8.83 - 8.88 (2H, m), 9.36 (1H, t, J = 5.7 Hz), 13.32 (1H, s).

Указанное в заголовке соединение получали, как в Примере 80, в виде бледно-желтых игл, выход 49%.Example 85
5-Bromo-2- (isonicotinoylamino) -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 80, as pale yellow needles, 49% yield.

Mp 207-211 ^o C.

Mass: 454 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.42 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.83 (1H, dd, J = 7.9, 1.5 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.95 (1H, d , J = 1.5 Hz), 7.75 - 7.83 (3H, m), 8.10 (1H, d, J = 2.2 Hz), 8.53 (1H, d, J = 9.0 Hz), 8.81 - 8.87 (2H, m), 9.48 (1H, t, J = 5.7 Hz), 12.61 (1H, s).

Mp 183-184 ^o C.

Mass: 451 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.54 - 1.75 (4H, m), 2.08 - 2.16 (2H, m), 2.20 - 2.28 (2H, m), 2.39 (1H, m), 2.51 (1H, m), 3.91 (3H, s), 4.53 ( 2H, d, J = 5.7 Hz), 6.92 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.22 (1H, dd, J = 8.4, 2.2 Hz), 7.39 ( 1H, d, J = 2.2 Hz), 7.70 (1H, dd, J = 8.0, 2.0 Hz), 7.86 (1H, d, J = 2.0 Hz), 8.79 (1H, d, J = 8.8 Hz), 11.57 ( 1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белых кристаллических гранул, выход 75%.Example 87
5-Bromo-2 - [(trans-4-cyanocyclohexanecarbonyl) amino] -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained as in Example 86 as white crystalline granules, yield 75%.

Mp 147-149 ^o C.

Mass: 484 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.54 - 1.73 (4H, m), 2.07 - 2.14 (2H, m), 2.19 - 2.27 (2H, m), 2.35 (1H, m), 2.50 (1H, m), 4.51 (2H, d, J = 5.5 Hz), 5.98 (2H, s), 6.47 (1H, m), 6.80 (2H, s), 6.84 (1H, s), 7.55 (1H, dd, J = 9.5, 2.2 Hz), 7.55 (1H, d , J = 2.2 Hz), 8.52 (1H, d, J = 9.5 Hz), 11.13 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белых игл, выход 60%.Example 88
2 - [(trans-4- (Acetoxy) cyclohexanecarbonyl) amino] -N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

The title compound was obtained, as in Example 86, as white needles, yield 60%.

Mp 194-196 ^o C.

Mass: 484 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.39 - 1.50 (2H, m), 1.62 - 1.74 (2H, m), 2.05 (3H, s), 2.05 - 2.15 (4H, m), 2.34 (1H, t, J = 11.7, 3.3 Hz), 3.91 ( 3H, s), 4.54 (2H, d, J = 5.9 Hz), 4.73 (1H, t, J = 11.0, 4.0 Hz), 6.82 (1H, t, J = 5.9 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.70 (1H, dd, J = 8.8, 2.0 Hz), 7.83 (1H, d , J = 2.0 Hz), 8.81 (1H, d, J = 8.8 Hz), 11.47 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде бледно-желтых игл, выход 17%.Example 89
5-Chloro-N- (3,4-methylenedioxybenzyl) -2 - [(trans-4-piperidinocyclohexanecarbonyl) amino] benzamide

The title compound was obtained, as in Example 86, as pale yellow needles, yield 17%.

Mp 162-163 ^o C.

Mass: 498 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.29 - 1.48 (4H, m), 1.50 - 1.63 (6H, m), 2.00 (2H, m), 2.10 (2H, m), 2.22 (1H, m), 2.32 (1H, m), 2.46 - 2.58 ( 4H, m), 4.51 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.51 (1H, t, J = 5.7 Hz), 6.77 - 6.85 (3H, m), 7.38 (1H, dd , J = 8.6, 2.6 Hz), 7.39 (1H, d, J = 2.6 Hz), 8.57 (1H, d, J = 8.6 Hz), 10.94 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белых игл, выход 2%.Example 90
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [(trans-4-piperidinocyclohexanecarbonyl) amino] benzamide

The title compound was obtained, as in Example 86, as white needles, yield 2%.

Mp 215-218 ^o C (decomp.).

Mass: 509 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.31 - 1.48 (4H, m), 1.51 - 1.64 (4H, m), 2.01 (2H, m), 2.11 (2H, m), 2.22 - 2.38 (2H, m), 2.48 - 2.56 (4H, m), 3.91 (3H, s), 4.54 (2H, d, J = 5.7 Hz), 6.71 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.22 (1H, dd, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 8.8, 2.0 Hz), 7.79 (1H, d, J = 2.0 Hz), 8.81 (1H, d, J = 8.8 Hz), 11.34 (1H, s )

2-Амино-N-(3-хлор-4-метоксибензил)-5-цианобензамид (1.2 г) растворяли в 10 мл пиридина и охлаждали льдом. К раствору прикапывали раствор 1.0 г транс-4-этоксикарбонилциклогексанкарбонилхлорида в 2 мл дихлорметана таким путем, чтобы температура реакционной смеси не превышала 10^oC. Полученную смесь перемешивали 4 ч, добавляли лед с водой и экстрагировали этилацетатом. Органическую фазу промывали 1н. соляной кислотой, водой, насыщенным водным раствором гидрохлорида натрия, водой и насыщенным водным раствором соли, сушили над безводным сульфатом магния и концентрировали в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: н-гексан/этилацетат (2:1)). Полученное твердое вещество промывали эфиром и получали 0.9 г указанного в заголовке соединения в виде белого порошка, выход 48%.Example 91
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

2-amino-N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide (1.2 g) was dissolved in 10 ml of pyridine and cooled with ice. A solution of 1.0 g of trans-4-ethoxycarbonylcyclohexanecarbonyl chloride in 2 ml of dichloromethane was added dropwise to the solution so that the temperature of the reaction mixture did not exceed 10 ^° C. The resulting mixture was stirred for 4 hours, ice-water was added and extracted with ethyl acetate. The organic phase was washed with 1N. hydrochloric acid, water, a saturated aqueous solution of sodium hydrochloride, water and a saturated aqueous solution of salt, were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate (2: 1)). The resulting solid was washed with ether and 0.9 g of the title compound was obtained as a white powder, yield 48%.

Mp 153-155 ^o C.

Mass: 498 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.64 (4H, m), 2.05 - 2.19 (4H, m), 2.28 - 2.38 (2H, m), 3.91 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.54 (2H, d, J = 5.7 Hz), 6.82 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 8.4, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.69 (1H, dd, J = 9.0, 1.8 Hz), 7.83 (1H, d, J = 1.8 Hz), 8.81 (1H, d, J = 9.0 Hz), 11.45 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде бледно-желтого порошка с выходом 61%.Example 92
5-Nitro-N- (3-chloro-4-methoxybenzyl-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was obtained, as in Example 91, as a pale yellow powder in 61% yield.

Mp 166-169 ^o C.

Mass: 518 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.47 - 1.66 (4H, m), 2.07 - 2.20 (4H, m), 2.29 - 2.40 (2H, m), 3.91 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.57 (2H, d, J = 5.7 Hz), 6.79 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.24 (1H, dd, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 8.30 (1H, dd, J = 9.3, 2.6 Hz), 8.39 (1H, d, J = 2.6 Hz), 8.88 (1H, d, J = 9.3 Hz), 11.64 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 83%.Example 93
5-Chloro-N- (3-chloro-4-methoxybenzyl) -2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was prepared as in Example 91 as a white powder in 83% yield.

Mp 122-125 ^o C.

Mass: 507 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.43 - 1.63 (4H, m), 2.06 - 2.14 (4H, m), 2.24 - 2.36 (2H, m), 3.91 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 6.67 (1H, t, J = 5.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.38 (1H, dd, J = 9.0, 2.4 Hz), 7.42 (1H, d, J = 2.4 Hz), 8.55 (1H, d, J = 9.0 Hz), 10.99 (1H, s).

 Example 94

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 94%.5-Chloro-2 - [(trans-4- (ethoxycarbonyl) cyclohexanecarbonyl) amino] - N- (2-methoxy-5-pyridylmethyl) benzamide

The title compound was obtained, as in Example 91, as a white powder in 94% yield.

Mp: 141-144 ^o C.

Mass: 474 (MH ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.45 - 1.63 (4H, m), 2.04 - 2.18 (4H, m), 2.24 - 2.36 (2H, m), 3.94 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.54 (2H, d, J = 5.7 Hz), 6.55 (1H, t, J = 5.7 Hz), 6.76 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 9.7, 2.4 Hz), 7.59 (1H, dd, J = 8.6, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.58 (1H, d, J = 9.7 Hz), 10.98 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 87%.Example 95
5-Chloro-N- (3-cyano-4-methoxybenzyl) -2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was obtained, as in Example 91, as a white powder in 87% yield.

Mp 157-160 ^o C.

Mass: 496 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.62 (4H, m), 2.03 - 2.17 (4H, m), 2.24 - 2.36 (2H, m), 3.94 (3H, s), 4.13 (2H, k, J = 7.1 Hz), 4.55 (2H, d, J = 5.9 Hz), 6.85 (1H, t, J = 5.9 Hz), 6.98 (1H, m), 7.39 (1H, dd, J = 9.0, 2.4 Hz), 7.44 (1H, d, J = 2.4 Hz), 7.53 - 7.58 (2H, m), 8.56 (1H, d, J = 9.0 Hz), 11.00 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 83%.Example 96
5-Chloro-N- (4-chloro-3-methoxybenzyl) -2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was prepared as in Example 91 as a white powder in 83% yield.

Mp 167-168 ^o C.

Mass: 507 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.04 - 2.18 (4H, m), 2.25 - 2.36 (2H, m), 3.92 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 4.58 (2H, d, J = 5.7 Hz), 6.54 (1H, t, J = 5.7 Hz), 6.88 (1H, dd, J = 8.1, 1.6 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.42 (1H, dd, J = 9.5, 2.2 Hz), 8.60 (1H, d, J = 9.5 Hz), 10.99 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 76%.Example 97
5-Bromo-N- (3-chloro-4-methoxybenzyl) -2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] -4-methoxybenzamide

The title compound was obtained, as in Example 91, as a white powder in 76% yield.

Mp 160 ^o C (decomp.).

Mass: 583 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.08 - 2.16 (4H, m), 2.27 - 2.37 (2H, m), 3.91 (3H, s), 3.95 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 4.51 (2H, d, J = 5.5 Hz), 6.41 (1H, t, J = 5.5 Hz), 6.92 (1H, d, J = 8.4 Hz) , 7.21 (1H, dd, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.61 (1H, s), 8.52 (1H, s), 11.62 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 71%.Example 98
5-Bromo-4-methoxy-N- (3-chloro-4-methoxybenzyl) -2- [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was obtained, as in Example 91, as a white powder in 71% yield.

Mp 171-173 ^o C.

Mass: 553 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3ЗH, t, J = 7.1 Hz), 1.43 - 1.62 (4H, m), 2.03 - 2.16 (4H, m), 2.24 - 2.35 (2H, m), 3.90 (3H, s), 4.13 (2H, k, J = 7.1 Hz), 4.52 (2H, d, J = 5.7 Hz), 6.79 (1H, t, J = 5.7 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 8.4, 2.2 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.50 (1H, dd, J = 9.0, 2.4 Hz), 7.57 (1H, d, J = 2.4 Hz), 8.47 (1H, d, J = 9.0 Hz), 11.01 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 72%.Example 99
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] -4-methoxybenzamide

The title compound was obtained, as in Example 91, as a white powder in 72% yield.

Mp 193-195 ^o C.

Mass: 526 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.06 - 2.19 (4H, m), 2.28 - 2.39 (2H, m), 3.91 (3H, s), 3.98 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.51 (2H, d, J = 5.7 Hz), 6.66 (1H, t, J = 5.7 Hz), 6.93 (1H, d, J = 8.6 Hz) , 7.22 (1H, dd, J = 8.6, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.75 (1H, s), 8.58 (1H, s), 11.92 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 89%.Example 100
N- (3-Chloro-4-methoxybenzyl) -5-dimethylsulfamoyl-2- [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was obtained as in Example 91 as a white powder in 89% yield.

Mp 197-198 ^o C.

Mass: 580 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.47 - 1.65 (4H, m), 2.06 - 2.19 (4H, m), 2.29 - 2.39 (2H, m), 2.67 (6H, s), 3.90 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.56 (2H, d, J = 5.9 Hz), 6.90 (1H, q, J = 8.4 Hz), 7.26 (1H, dd, J = 8.4, 2.2 Hz), 7.32 (1H, t, J = 5.9 Hz), 7.42 (1H, d, J = 2.2 Hz), 7.79 (1H, dd, J = 9.0, 2.2 Hz), 7.99 (1H, d, J = 2.2 Hz), 8.88 (1H, d, J = 9.0 Hz), 11.63 (1H, s).

Указанное в заголовке соединение получали, как в Примере 91, в виде белого порошка с выходом 44%.Example 101
N- (3-Chloro-4-methoxybenzyl) -2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] -5-methylsulfamoylbenzamide

The title compound was prepared as in Example 91 as a white powder in 44% yield.

Mp 190-191 ^o C.

Mass: 566 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.46 - 1.65 (4H, m), 2.06 - 2.18 (4H, m), 2.29 - 2.39 (2H, m), 2.61 (3H, d, J = 5.3 Hz) , 3.89 (3H, s), 4.14 (2H, q, J = 7.1 Hz), 4.53 (2H, d, J = 5.9 Hz), 4.65 (1H, q, J = 5.3 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.20 (1H, t, J = 5.9 Hz), 7.23 (1H, dd, J = 8.6, 2.2 Hz), 7.40 (1H, d, J = 2.2 Hz), 7.84 (1H, dd, J = 9.0, 2.2 Hz), 8.03 (1H, d, J = 2.2 Hz), 8.83 (1H, d, J = 9.0 Hz), 11.58 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 85%.Example 102
2 - [(trans-4- (Ethoxycarbonyl) cyclohexanecarbonyl) amino] -N- (3,4-methylenedioxybenzyl) -5- (1-pyrazolyl) benzamide

The title compound was prepared as in Example 86 as a white powder in 85% yield.

Mp 197-201 ^o C.

Mass: 519 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.46 - 1.66 (4H, m), 2.08 - 2.18 (4H, m), 2.27 - 2.38 (2H, m), 4.14 (2H, q, J = 7.1 Hz) , 4.52 (2H, d, J = 5.7 Hz), 5.96 (2H, s), 6.47 (1H, dd, J = 2.4, 1.6 Hz), 6.78 (1H, d, J = 7.9 Hz), 6.80 (1H, dd, J = 7.9, 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz), 6.85 (1H, m), 7.59 (1H, dd, J = 9.2, 2.6 Hz), 7.68 (1H, d, J = 1.6 Hz), 7.89 (1H, d, J = 2.6 Hz), 7.95 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 9.2 Hz), 11.18 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 69%.Example 103
2 - [[trans-4- (Ethoxycarbonyl) cyclohexanecarbonyl] amino] -N- (3,4-methylenedioxybenzyl) -5- (1,2,4-triazol-1-yl) benzamide

The title compound was prepared as in Example 86 as a white powder in 69% yield.

Mp 204-206 ^o C.

Mass: 520 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.27 (3H, t, J = 7.1 Hz), 1.45 - 1.65 (4H, m), 2.05 - 2.19 (4H, m), 2.28 - 2.38 (2H, m), 4.14 (2H, q, J = 7.1 Hz) , 4.55 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.79 (1H, d, J = 7.9 Hz), 6.82 (1H, dd, J = 7.9, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 6.91 (1H, t, J = 5.7 Hz), 7.64 (1H, dd, J = 9.2, 2.6 Hz), 7.86 (1H, d, J = 2.6 Hz), 8.05 (1H, s), 8.49 (1H, s), 8.79 (1H, d, J = 9.2 Hz), 11.21 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 63%.Example 104
2 - [[trans-4- (Ethoxycarbonyl) cyclohexanecarbonyl] amino] -N- (3,4-methylenedioxybenzyl) -5-trifluoromethoxybenzamide

The title compound was obtained, as in Example 86, as a white powder in 63% yield.

Mp 179-180 ^o C.

Mass: 537 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.05 - 2.17 (4H, m), 2.25 - 2.37 (2H, m), 4.13 (2H, q, J = 7.1 Hz) , 4.52 (2H, d, J = 5.7 Hz), 5.97 (2H, s), 6.53 (1H, t, J = 5.7 Hz), 6.79 (1H, d, J = 7.9 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.84 (1H, s), 7.28 (1H, d, J = 2.7 Hz), 7.32 (1H, dd, J = 9.2, 2.6 Hz), 8.66 (1H, d, J = 9.2 Hz) 11.03 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 36%.Example 105
5-cyano-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] - amino] -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 86, as a white powder in 36% yield.

Mp 150-153 ^o C.

Mass: 478 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.64 (4H, m), 2.05 - 2.18 (4H, m), 2.28 - 2.38 (2H, m), 4.14 (2H, q, J = 7.1 Hz) , 4.52 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.75 (1H, t, J = 5.7 Hz), 6.80 (1H, dd, J = 7.9, 0.7 Hz), 6.83 (1H, dd, J = 7.9, 1.3 Hz), 6.85 (1H, dd, J = 1.3, 0.7 Hz), 7.69 (1H, dd, J = 9.0, 2.0 Hz), 7.81 (1H, d, J = 2.0 Hz), 8.80 (1H, d, J = 9.0 Hz), 11.46 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 67%.Example 106
5-Bromo-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] - 4-methoxy-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 86, as a white powder in 67% yield.

Mp 194-195 ^o C.

Mass: 561 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.66 (4H, m), 2.08 - 2.16 (4H, m), 2.27 - 2.37 (2H, m), 3.95 (3H, s), 4.13 (2H, k, J = 7.1 Hz), 4.50 (2H, d, J = 5.5 Hz), 5.97 (2H, s), 6.35 (1H, t, J = 5.5 Hz), 6.80 (2H, s), 6.84 (1H, s), 7.60 (1H, s), 8.52 (1H, s), 11.65 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде белого порошка с выходом 67%.Example 107
4-Bromo-7 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] - N- (3,4-methylenedioxybenzyl) isoindolin-1-one

The title compound was obtained, as in Example 86, as a white powder in 67% yield.

Mp 135-137 ^o C.

Mass: 543 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.68 (4H, m), 2.10 - 2.20 (4H, m), 2.29 - 2.41 (2H, m), 4.14 (2H, q, J = 7.1 Hz) , 4.17 (2H, s), 4.66 (2H, s), 5.96 (2H, s), 6.76 - 6.82 (3H, m), 7.55 (1H, d, J = 8.8 Hz), 8.44 (1H, d, J = 8.8 Hz), 10.42 (1H, s).

Указанное в заголовке соединение получали, как в Примере 86, в виде бесцветного масла с выходом 86%.Example 108
5-Bromo-8 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] - amino] -N- (3,4-methylenedioxybenzyl) -1,2,3,4-tetrahydroisoquinolin-1-one

The title compound was obtained, as in Example 86, as a colorless oil in 86% yield.

Mass: 557 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.46 - 1.67 (4H, m), 2.06 - 2.17 (4H, m), 2.28 - 2.38 (2H, m), 3.01 (2H, t, J = 6.6 Hz) , 3.46 (2H, t, J = 6.6 Hz), 4.13 (2H, s, J = 7.1 Hz), 4.67 (2H, s), 5.96 (2H, s), 6.77 (1H, dd, J = 7.2, 1.3 Hz), 6.79 (1H, d, J = 7.2 Hz), 6.81 (1H, d, J = 1.3 Hz), 7.60 (1H, d, J = 9.0 Hz), 8.57 (1H, d, J = 9.0 Hz) 12.38 (1H, s).

2-(транс-4-Ацетоксициклогексанкарбониламино)-N-(3-хлор-4- метоксибензил)-5-цианобензамид (0.9 г) растворяли в смешанном растворителе, содержащем 10 мл этанола и 10 мл тетрагидрофурана, и добавляли 6 мл 1н. гидроксида натрия. Смесь перемешивали при комнатной температуре 2 ч, добавляли воду и экстрагировали смесью этилацетат/тетрагидрофуран/этанол. Органическую фазу промывали насыщенным водным раствором соли, сушили над безводным сульфатом магния и растворитель отгоняли в вакууме. Твердое вещество промывали эфиром, перекристаллизовывали из водного этанола и получали 0.33 г указанного в заголовке соединения в виде белых игл, выход 39%.Example 109
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [(trans-4-hydroxycyclohexanecarbonyl) amino] benzamide

2- (trans-4-acetoxycyclohexanecarbonylamino) -N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide (0.9 g) was dissolved in a mixed solvent containing 10 ml of ethanol and 10 ml of tetrahydrofuran, and 6 ml of 1N was added. sodium hydroxide. The mixture was stirred at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate / tetrahydrofuran / ethanol. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The solid was washed with ether, recrystallized from aqueous ethanol to give 0.33 g of the title compound as white needles, yield 39%.

Mp 164-165 ^o C.

Mass: 442 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.14 - 1.26 (2H, m), 1.35 - 1.47 (2H, m), 1.83 - 1.93 (4H, m), 3.35 (1H, m), 3.84 (3H, s), 4.42 (2H, d, J = 5.5 Hz), 4.61 (1H, d, J = 4.4 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.30 (1H, dd, J = 8.4, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.94 (1H, dd, J = 8.8, 2.0 Hz), 8.25 (1H, d, J = 2.0 Hz), 8.58 (1H, d, J = 8.8 Hz), 9.24 (1H, t, J = 5.5 Hz), 11.54 (1H, s).

N-(3-Хлор-4-метоксибензил)-5-циано-2-(транс-4- этоксикарбонилциклогексанкарбониламино)бензамид (0.9 г) растворяли в смешанном растворителе, содержащем 10 мл этанола и 10 мл тетрагидрофурана, и добавляли 6 мл 1н. гидроксида натрия. Смесь перемешивали при комнатной температуре 8 ч и добавляли воду и этилацетат. Водную фазу отделяли, а фазу этилацетата экстрагировали водой. Обе водные фазы объединяли и подкисляли 1н. соляной кислотой. Образующийся осадок отделяли фильтрованием, перекристаллизовывали из водного этанола и получали 0.42 г указанного в заголовке соединения в виде белых игл, выход 72%.Example 110
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

N- (3-Chloro-4-methoxybenzyl) -5-cyano-2- (trans-4-ethoxycarbonylcyclohexanecarbonylamino) benzamide (0.9 g) was dissolved in a mixed solvent containing 10 ml of ethanol and 10 ml of tetrahydrofuran, and 6 ml of 1N was added. sodium hydroxide. The mixture was stirred at room temperature for 8 hours and water and ethyl acetate were added. The aqueous phase was separated, and the ethyl acetate phase was extracted with water. Both aqueous phases were combined and acidified with 1N. hydrochloric acid. The precipitate formed was filtered off, recrystallized from aqueous ethanol to give 0.42 g of the title compound as white needles, yield 72%.

Mp 223-227 ^o C.

Mass: 470 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.48 (4H, m), 1.89 - 2.02 (4H, m), 2.18 (1H, m), 2.31 (1H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz) , 7.12 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 8.6, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 7.93 (1H, dd, J = 8.8, 2.0 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J = 8.8 Hz), 9.43 (1H, t, J = 5.7 Hz), 11.57 (1H, s), 12.10 (1H, with).

Указанное в заголовке соединение получали, как в Примере 110, в виде белого порошка с выходом 64%.Example 111
1 - [[4-Bromo-2 - [(3-chloro-4-methoxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylic acid

The title compound was obtained as in Example 110 as a white powder in 64% yield.

Mp 259 ^o C (decomp.).

Mass: 526 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.48 (2H, m), 1.87 (2H, m), 2.49 (1H, m), 2.98 (1H, m), 3.84 (3H, s), 3.91 (2H, m), 4.40 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.6 Hz), 7.28 (1H, dd, J = 8.6, 2.0 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.94 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 9.2 Hz), 9.38 (1H, t, J = 5.7 Hz), 11.04 (1H, s), 12.30 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 77%.Example 112
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - 5-chloro-N- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained as in Example 110, in the form of white needles in a yield of 77%.

Mp 233-235 ^o C.

Mass: 478 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.47 (4H, m), 1.85 - 2.02 (4H, m), 2.13 - 2.29 (2H, m), 3.84 (3H, s), 4.40 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.55 (1H, dd, J = 9.0, 2.4 Hz), 7.82 ( 1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 9.0 Hz), 9.35 (1H, t, J = 5.7 Hz), 11.15 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл, выход 58%.Example 113
5-Bromo-2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained as in Example 110, in the form of white needles, yield 58%.

Mp 247-250 ^o C.

Mass: 523 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.46 (4H, m), 1.88 - 2.02 (4H, m), 2.13 - 2.29 (2H, m), 3.84 (3H, s), 4.40 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 7.67 (1H, dd, J = 9.0, 2.2 Hz), 7.94 ( 1H, d, J = 2.2 Hz), 8.33 (1H, d, J = 9.0 Hz), 9.35 (1H, t, J = 5.7 Hz), 11.16 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде бледно-желтых игл с выходом 65%.Example 114
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3-chloro-4-methoxybenzyl) -5-nitrobenzamide

The title compound was obtained, as in Example 110, as pale yellow needles in 65% yield.

Mp 235-244 ^o C (decomp.).

Mass: 490 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.50 (4H, m), 1.91 - 2.04 (4H, m), 2.13 (1H, m), 2.34 (1H, m), 3.84 (3H, s), 4.45 (2H, d, J = 5.3 Hz) , 7.12 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4, 2.2 Hz), 7.44 (1H, d, J = 2.2 Hz), 8.38 (1H, dd, J = 9.3, 2.7 Hz), 8.68 (1H, d, J = 9.3 Hz), 8.69 (1H, d, J = 2.7 Hz), 9.68 (1H, t, J = 5.3 Hz), 11.76 (1H, s), 12.10 (1H, with).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 67%.Example 115
5-Bromo-2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3-chloro-4-methoxybenzyl) -4-methoxybenzamide

The title compound was obtained, as in Example 110, as white needles in 67% yield.

Mp 223-229 ^o C.

Mass: 555 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.50 (4H, m), 1.90 - 2.02 (4H, m), 2.18 (1H, m), 2.26 (1H, m), 3.83 (3H, s), 3.87 (3H, s), 4.39 (2H, d, J = 5.7 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.27 (1H, dd, J = 8.4, 2.2 Hz), 7.39 (1H, d, J = 2.2 Hz), 8.09 (1H, s), 8.42 (1H, s), 9.24 (1H, t, J = 5.7 Hz), 11.92 (1H, s), 12.01 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 51%.Example 116
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3-chloro-4-methoxybenzyl) -4-methoxy-5-cyanobenzamide

The title compound was obtained as in Example 110, in the form of white needles in 51% yield.

Mp 255-257 ^o C.

Mass: 500 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.33 - 1.51 (4H, m), 1.91 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 3.84 (3H, s), 3.93 (3H, s), 4.41 (2H, d, J = 5.5 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 2.2 Hz), 8.27 (1H, s), 8.47 (1H, s), 9.28 (1H, t, J = 5.7 Hz), 12.01 (1H, s), 12.19 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 68%.Example 117
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3-chloro-4-methoxybenzyl) -5-dimethylsulfamoylbenzamide

The title compound was obtained, as in Example 110, as white needles in 68% yield.

Mp 245-246 ^o C.

Mass: 552 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.46 (4H, m), 1.89 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 2.63 (6H, s), 3.84 (3H, s), 4.45 (2H, d, J = 5.7 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.29 (1H, dd, J = 8.4, 2.0 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.86 (1H, dd, J = 8.8, 2.2 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.64 (1H, d, J = 8.8 Hz), 9.58 (1H, t, J = 5.7 Hz), 11.50 (1H, s), 12.09 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 38%.Example 118
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3-chloro-4-methoxybenzyl) -5-methylsulfamoylbenzamide

The title compound was prepared as in Example 110 as white needles in 38% yield.

Mp 247-249 ^o C.

Mass: 538 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.31 - 1.48 (4H, m), 1.88 - 2.03 (4H, m), 2.18 (1H, m), 2.30 (1H, m), 2.41 (3H, d, J = 4.9 Hz), 3.84 (3H, s) , 4.45 (2H, d, J = 5.9 Hz), 7.12 (1H, d, J = 8.4 Hz), 7.30 (1H, dd, J = 8.4, 2.2 Hz), 7.40 (1H, q, J = 4.9 Hz) , 7.42 (1H, d, J = 2.2 Hz), 7.86 (1H, dd, J = 8.8, 2.2 Hz), 8.10 (1H, d, J = 2.2 Hz), 8.55 (1H, d, J = 8.8 Hz) 9.53 (1H, t, J = 5.9 Hz), 11.30 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 78%.Example 119
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -5-chloro-N - [(2-methoxy-5-pyridyl) methyl] benzamide

The title compound was obtained, as in Example 110, as white needles in 78% yield.

Mp 219-221 ^o C.

Mass: 446 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.46 (4H, m), 1.85 - 2.02 (4H, m), 2.13 - 2.29 (2H, m), 3.83 (3H, s), 4.41 (2H, d, J = 5.7 Hz), 6.80 (1H, d, J = 8.6 Hz), 7.54 (1H, dd, J = 9.0, 2.4 Hz), 7.70 (1H, dd, J = 8.6, 2.4 Hz), 7.81 (1H, d, J = 2.4 Hz), 8.16 ( 1H, d, J = 2.4 Hz), 8.38 (1H, d, J = 9.0 Hz), 9.33 (1H, t, J = 5.7 Hz), 11.13 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 77%.Example 120
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -5-chloro-N- (3-cyano-4-methoxybenzyl) benzamide

The title compound was obtained as in Example 110, in the form of white needles in a yield of 77%.

Mp 190-193 ^o C.

Mass: 470 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.46 (4H, m), 1.84 - 2.02 (4H, m), 2.12 - 2.28 (2H, m), 3.90 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 7.23 (1H, d, J = 8.8 Hz), 7.55 (1H, dd, J = 9.0, 2.6 Hz), 7.65 (1H, dd, J = 8.8, 2.4 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.78 ( 1H, d, J = 2.6 Hz), 8.36 (1H, d, J = 9.0 Hz), 9.34 (1H, t, J = 5.7 Hz), 11.10 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 38%.Example 121
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - 5-chloro-N- (4-chloro-3-methoxybenzyl) benzamide

The title compound was prepared as in Example 110 as white needles in 38% yield.

Mp 224-225 ^o C.

Mass: 479 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.29 - 1.46 (4H, m), 1.85 - 2.01 (4H, m), 2.13 - 2.28 (2H, m), 3.86 (3H, s), 4.47 (2H, d, J = 5.9 Hz), 6.93 (1H, dd, J = 8.1, 1.5 Hz), 7.15 (1H, d, J = 1.5 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.56 (1H, dd, J = 9.0, 2.4 Hz), 7.85 ( 1H, d, J = 2.4 Hz), 8.39 (1H, d, J = 9.0 Hz), 9.39 (1H, t, J = 5.9 Hz), 11.16 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белого порошка с выходом 62%.Example 122
1 - [[4-Bromo-2 - [(3,4-methylenedioxybenzyl) carbamoyl] phenyl] carbamoyl] piperidine-4-carboxylic acid

The title compound was obtained, as in Example 110, as a white powder in 62% yield.

Mp 276-280 ^o C (decomp.).

Mass: 504 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.47 (2H, m), 1.86 (2H, m), 2.49 (1H, m), 2.98 (1H, m), 3.91 (2H, m), 4.37 (2H, d, J = 5.7 Hz), 5.99 (2H , s), 6.81 (1H, dd, J = 7.9, 1.6 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.92 (1H, d, J = 7.9 Hz), 7.61 (1H, dd, J = 9.2, 2.4 Hz), 7.94 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 9.2 Hz), 9.35 (1H, t, J = 5.7 Hz), 11.07 (1H, s), 12.30 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 48%.Example 123
4-Bromo-7 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3,4-methylenedioxybenzyl) isoindolin-1-one

The title compound was obtained, as in Example 110, as white needles in 48% yield.

Mp 261-263 ^o C.

Mass: 515 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.34 - 1.54 (4H, m), 1.95 - 2.06 (4H, m), 2.21 (1H, m), 2.37 (1H, m), 4.29 (2H, s), 4.63 (2H, s), 6.00 (2H, s), 6.83 (1H, dd, J = 7.9, 1.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.71 (1H, d, J = 8.8 Hz), 8.28 (1H, d, J = 8.8 Hz), 10.38 (1H, s), 12.01 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 45%.Example 124
5-Bromo-8 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3,4-methylenedioxybenzyl) -1,2,3,4-tetrahydro-1-isoquinolinone

The title compound was obtained, as in Example 110, as white needles in 45% yield.

Mp 241-244 ^o C.

Mass: 529 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ δ:
1.33 - 1.52 (4H, m), 1.92 - 2.04 (4H, m), 2.20 (1H, m), 2.28 (1H, m), 2.97 (2H, t, J = 6.8 Hz), 3.50 (2H, t, J = 6.8 Hz), 4.64 (2H, s), 6.00 (2H, s), 6.83 (1H, dd, J = 8.1, 1.5 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.92 (1H, d, J = 1.5 Hz), 7.73 (1H, d, J = 9.0 Hz), 8.45 (1H, d, J = 9.0 Hz), 12.10 (1H, s), 12.39 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 72%.Example 125
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] - N- (3,4-methylenedioxybenzyl) -5-trifluoromethoxybenzamide

The title compound was obtained, as in Example 110, as white needles in 72% yield.

Mp 245-250 ^o C.

Mass: 509 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.31 - 1.48 (4H, m), 1.86 - 2.03 (4H, m), 2.14 - 2.32 (2H, m), 4.39 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.82 (1H, dd, J = 8.1, 1.6 Hz), 6.87 (1H, d, J = 8.1 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.52 (1H, dd, J = 9.2, 2.8 Hz), 7.76 ( 1H, d, J = 2.8 Hz), 8.46 (1H, d, J = 9.2 Hz), 9.33 (1H, t, J = 5.7 Hz), 11.22 (1H, s), 12.09 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 65%.Example 126
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3,4-methylenedioxybenzyl) -5- (1-pyrazolyl) benzamide

The title compound was prepared as in Example 110 as white needles in 65% yield.

Mp 219-221 ^o C.

Mass: 491 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.49 (4H, m), 1.89 - 2.03 (4H, m), 2.15 -2.31 (2H, m), 4.42 (2H, d, J = 5.9 Hz), 5.99 (2H, s), 6.56 (1H, dd, J = 2.4, 1.8 Hz), 6.84 (1H, dd, J = 7.8, 1.5 Hz), 6.87 (1H, d, J = 7.8 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.76 ( 1H, d, J = 1.8 Hz), 7.94 (1H, dd, J = 9.0, 2.6 Hz), 8.16 (1H, d, J = 2.6 Hz), 8.48 (1H, d, J = 9.0 Hz), 8.48 ( 1H, d, J = 2.4 Hz), 9.38 (1H, t, J = 5.9 Hz), 11.18 (1H, s), 12.08 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 73%.Example 127
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3,4-methylenedioxybenzyl) -5- (1,2,4-triazol-1-yl) benzamide

The title compound was obtained, as in Example 110, as white needles in 73% yield.

Mp 278-281 ^o C (decomp.).

Mass: 492 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.50 (4H, m), 1.90 - 2.03 (4H, m), 2.15 - 2.33 (2H, m), 4.43 (2H, d, J = 5.7 Hz), 5.99 (2H, s), 6.84 (1H, dd, J = 8.1, 1.1 Hz), 6.87 (1H, d, J = 8.1 Hz), 6.95 (1H, d, J = 1.1 Hz), 7.96 (1H, dd, J = 9.0, 2.4 Hz), 8.21 ( 1H, d, J = 2.4 Hz), 8.25 (1H, s), 8.54 (1H, d, J = 9.0 Hz), 9.24 (1H, s), 9.37 (1H, t, J = 5.7 Hz), 11.23 ( 1H, s), 12.09 (1H, s).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 72%.Example 128
2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -5-cyano-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 110, as white needles in 72% yield.

Mp 238-241 ^o C (decomp.).

Mass: 450 (MH ⁺ ).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.48 (4H, m), 1.89 - 2.03 (4H, m), 2.19 (1H, m), 2.31 (1H, m), 4.40 (2H, d, J = 5.7 Hz), 5.99 (2H, s) , 6.83 (1H, dd, J = 7.9, 1.5 Hz), 6.87 (1H, d, J = 7.9 Hz), 6.95 (1H, d, J = 1.5 Hz), 7.93 (1H, dd, J = 8.8, 2.0 Hz), 8.26 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J = 8.8 Hz), 9.40 (1H, t, J = 5.7 Hz), 11.61 (1H, s), 12.09 (1H, with).

Указанное в заголовке соединение получали, как в Примере 110, в виде белых игл с выходом 26%.Example 129
5-Bromo-2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -4-methoxy-N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 110, as white needles in 26% yield.

Mp 245-249 ^o C.

Mass: 533 (MH ⁺ ).

⁺ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.32 - 1.50 (4H, m), 1.90 - 2.18 (1H, m), 2.26 (1H, m), 3.87 (3H, s), 4.37 (2H, d, J = 5.7 Hz), 5.99 (2H, s) , 6.80 (1H, dd, J = 7.9, 1.6 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 8.10 (1H, s), 8.42 (1H, s), 9.21 (1H, t, J = 5.7 Hz), 11.96 (1H, s), 12.01 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 56%.Example 130
5-Chloro-2- (2,5-dimethoxybenzamido) -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 34, in the form of white crystals with a yield of 56%.

Mass: 469 (MH ⁺ ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
3.84 (3H, s), 4.04 (3H, s), 4.52 (2H, d, J = 5.7 Hz), 5.94 (2H, s), 6.34 (1H, t, J = 5.7 Hz), 6.73 - 6.84 (3H , m), 6.95 (1H, d, J = 9.0 Hz), 7.06 (1H, dd, J = 3.1, 9.0 Hz), 7.38 - 7.44 (2H, m), 7.77 (1H, d, J = 3.1 Hz) 11.71 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде светло-коричневых кристаллов с выходом 78%.Example 131
4-amino-5-bromo-2 - [(isonicotinoyl) amino] -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 34, in the form of light brown crystals with a yield of 78%.

¹ H-NMR (400, DMSO-d ₆ ) δ:
4.38 (2H, d, J = 5.7 Hz), 5.98 (2H, s), 6.19 (2H, w s), 6.80 (1H, dd, J = 1.6, 7.9 Hz), 6.86 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 1.6 Hz), 7.80 (2H, d, J = 5.9 Hz), 8.05 (1H, s), 8.22 (1H, s), 8.84 (2H, d, J = 5.9 Hz), 9.10 (1H, t, J = 5.7 Hz), 13.35 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белого кристаллического порошка с выходом 79%.Example 132
4-amino-5-bromo-2 - [(4-tert-butylbenzenesulfonyl) amino] - N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 34, as a white crystalline powder in 79% yield.

Mp 234-235 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.25 (9H, s), 4.28 (2H, d, J = 5.8 Hz), 6.00 (2H, w s), 6.78 (1H, dd, J = 1.6, 8.1 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.88 (1H, d, J = 8.1 Hz), 7.00 (1H, s), 7.49 - 7.54 (2H, m), 7.66 - 7.71 (2H, m), 7.86 (1H, s), 8.97 (1H , t, J = 5.8 Hz), 12.68 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 41%.Example 133
4-amino-5-bromo-2- (methanesulfonyl) amino-N- (3,4-methylenedioxy benzyl) benzamide

The title compound was obtained, as in Example 34, as white crystals in 41% yield.

Mp 178-180 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
3.08 (3H, s), 3.83 (3H, s), 4.33 (2H, d, J = 5.7 Hz), 6.17 (2H, w s), 6.94 (1H, s), 7.11 (1H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 2.0, 8.6 Hz), 7.36 (1H, d, J = 2.0 Hz), 8.00 (1H, s), 9.07 (1H, t, J = 5.7 Hz), 11.80 ( 1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 69%.Example 134
5-bromo-2-benzene sulfonylamido-N- (3,4-methylenedioxybenzyl) - benzamide

The title compound was obtained, as in Example 34, in the form of white crystals with a yield of 69%.

Mp 172-173 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.31 (2H, d, J = 5.9 Hz), 6.77 (1H, dd, J = 1.6 Hz, 7.9 Hz), 6.87 (1H, d, J = 1.6 Hz), 6.89 (1H, d, J = 7.9 Hz) , 7.45 - 7.55 (3H, m), 7.60 - 7.74 (4H, m), 9.33 (1H, m), 11.56 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 24%.Example 135
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [[((S) -5-oxo-2-tetrahydrofurancarbonyl] amino] benzamide

The title compound was obtained, as in Example 34, as white crystals in 24% yield.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
2.23 - 2.35 (1H, m), 2.52 - 2.63 (3H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.12 - 5.17 (1H, m), 7.12 (1H, d, J = 8.6 Hz), 7.32 (1H, dd, J = 8.0, 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.00 (1H, dd, J = 1.6, 8.9 Hz), 8.30 ( 1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 9.41 (1H, t, J = 5.7 Hz), 12.02 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 42%.Example 136
N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [((R) -5-oxo-2-tetrahydrofurancarbonyl) amino] benzamide

The title compound was obtained, as in Example 34, in the form of white crystals with a yield of 42%.

Mp 231-232 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
2.23 - 2.35 (1H, m), 2.52 - 2.63 (3H, m), 3.84 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.12 - 5.17 (1H, m), 7.12 (1H, d, J = 8.6 Hz), 7.32 (1H, dd, J = 8.0, 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.00 (1H, dd, J = 1.6, 8.9 Hz), 8.30 ( 1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 8.30 (1H, d, J = 1.6 Hz), 8.60 (1H, d, J = 8.9 Hz), 9.41 (1H, t, J = 5.7 Hz), 12.02 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 59%.Example 137
4-amino-5-bromo-2 - [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] -N- (3,4-methylenedioxybenzyl) benzamide

The title compound was obtained, as in Example 34, in the form of white crystals with a yield of 59%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.44 - 1.64 (4H, m), 2.06 - 2.14 (4H, m), 2.25 - 2.36 (2H, m), 4.13 (2H, q, J = 7.1 Hz) , 4.42 - 4.49 (4H, m), 5.97 (2H, s), 6.30 (1H, t, J = 5.5 Hz), 5.97 (2H, s), 6.83 (1H, s); 7.49 (1H, s), 8.20 (1H, s), 11.57 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 67%.Example 138
4-amino-5-bromo-N- (3-chloro-4-methoxybenzyl) -2- [[trans-4- (ethoxycarbonyl) cyclohexanecarbonyl] amino] benzamide

The title compound was obtained, as in Example 34, in the form of white crystals with a yield of 67%.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.26 (3H, t, J = 7.1 Hz), 1.42 - 1.64 (4H, m), 2.24 - 2.37 (2H, m), 3.91 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 4.46 (2H, w s), 4.49 (2H, d, J = 5.6 Hz), 6.30 (1H, t, J = 5.6 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 2.2, 8.4 Hz), 7.37 (1H, d, J = 2.2 Hz), 7.49 (1H, s), 8.21 (1H, s), 11.54 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 75%.Example 139
4-amino-5-brom-2 - [(trans-4-carboxycyclohexanecarbonyl) - amino] -N- (3,4-methylenedioxybenzyl] benzamide

The title compound was obtained, as in Example 34, as white crystals in 75% yield.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.47 (4H, m), 1.90 - 1.99 (4H, m), 2.13 - 2.24 (2H, m), 4.33 (2H, d, J = 5.6 Hz), 5.98 (2H, s), 6.00 (2H, w s), 6.77 (1H, dd, J = 1.6, 8.1. Hz), 6.88 (1H, d, J = 1.6 Hz), 7.90 (1H, s), 8.04 (1H, s), 8.95 (1H, t , J - 4.0 Hz), 11.93 (1H, s).

Указанное в заголовке соединение получали, как в Примере 34, в виде белых кристаллов с выходом 64%.Example 140
4-amino-5-bromo-2 - [(trans-4-carboxycyclohexanecarbonyl) amino] -N- (3-chloro-4-methoxybenzyl) benzamide

The title compound was obtained, as in Example 34, as white crystals in 64% yield.

Mp 274-276 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.30 - 1.47 (4H, m), 1.90 - 1.98 (4H, m), 2.12 -2.23 (2H, m), 3.83 (3H, s), 4.35 (2H, d, J = 5.6 Hz), 6.01 (2H, w s), 7.11 (1H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 8.6, 2.2 Hz), 7.36 (1H, d, J = 2.2 Hz), 7.90 (1H, s), 8.03 (1H, s), 8.98 (1H, t, J = 5.4 Hz), 11.89 (1H, s).

N-(3-Хлор-4-метоксибензил)-5-циано-2-[[(R)-5-оксо-2- тетрагидрофуранкарбонил] амино] бензамид (500 мг) растворяли в 2.5 мл 1,4-диоксана и добавляли 2.5 мл концентрированного водного аммиака. Смесь кипятили с обратным холодильником и концентрировали. Остаток очищали колоночной хроматографией на силикагеле (растворитель: этилацетат) и получали 150 мг указанного в заголовке соединения в виде белых кристаллов, выход 29%.Example 141
2 - [[(R) -4-Carbamoyl-2-hydroxybutyryl] amino] -N- (3-chloro-4-methoxybenzyl) -5-cyanobenzamide

N- (3-Chloro-4-methoxybenzyl) -5-cyano-2 - [[(R) -5-oxo-2-tetrahydrofurancarbonyl] amino] benzamide (500 mg) was dissolved in 2.5 ml of 1,4-dioxane and added 2.5 ml of concentrated aqueous ammonia. The mixture was refluxed and concentrated. The residue was purified by silica gel column chromatography (solvent: ethyl acetate) to obtain 150 mg of the title compound as white crystals, yield 29%.

Mp 168-170 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
1.68 - 1.80 (1H, m), 1.95 - 2.05 (1H, m), 2.12 - 2.30 (2H, m), 3.84 (3H, s), 4.05 - 4.13 (1H, m), 4.40 - 4.47 (2H, m ), 6.35 (1H, sh s), 6.79 (1H, sh s), 7.09 - 7.15 (1H, m), 7.29 - 7.42 (2H, m), 7.43 (1H, d, J = 2.0 Hz), 7.96 ( 1H, dd, J = 2.0, 8.8 Hz), 8.27 (1H, d, J = 2.0 Hz), 8.77 (1H, d, J = 8.8 Hz), 9.40 (1H, t, J = 5.7 Hz), 12.16 ( 1H, w s).

4-Hитроантраниловую кислоту (7.0 г), пиперониламин (6.42 г), N,N'-дициклoгeкcилкapбoдиимид (8.78 г) и 1-гидроксибензтриазол (5.75 г) добавляли в 500 мл ацетонитрила. Смесь нагревали 3 ч при 60^oC, охлаждали и отфильтровывали образующиеся кристаллы. Фильтрат концентрировали и экстрагировали этилацетатом. Этилацетат удаляли и получали неочищенные кристаллы. К кристаллам добавляли этанол (50 мл), диметилформамид (50 мл) и оксид платины (50 мг). Полученную смесь подвергали каталитическому гидрированию при повышенном давлении в течение 2 ч при комнатной температуре. Катализатор отделяли фильтрованием и растворитель отгоняли. К остатку добавляли дихлорметан, чтобы провести кристаллизацию. Кристаллы отделяли фильтрованием, сушили и получали 4.63 г указанного в заголовке соединения в виде серых кристаллов, выход 42%.Example 142
2,4-Diamino-N- (3,4-methylenedioxybenzyl) benzamide

4-Nitroantranilic acid (7.0 g), piperonylamine (6.42 g), N, N'-dicyclohexylcarbodiimide (8.78 g) and 1-hydroxybenzotriazole (5.75 g) were added to 500 ml of acetonitrile. The mixture was heated at 60 ^° C. for 3 hours, cooled and the resulting crystals were filtered off. The filtrate was concentrated and extracted with ethyl acetate. Ethyl acetate was removed and crude crystals were obtained. Ethanol (50 ml), dimethylformamide (50 ml) and platinum oxide (50 mg) were added to the crystals. The resulting mixture was subjected to catalytic hydrogenation at elevated pressure for 2 hours at room temperature. The catalyst was filtered off and the solvent was distilled off. Dichloromethane was added to the residue to crystallize. The crystals were separated by filtration, dried, and 4.63 g of the title compound were obtained as gray crystals, yield 42%.

Mp 180-182 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.25 (2H, d, J = 6.0 Hz), 5.28 (2H, s), 5.76 - 5.80 (2H, m), 5.96 (2H, s), 6.39 (2H, s), 6.81 - 6.86 (2H, m) , 7.28 (1H, d, J = 9.2 Hz), 8.21 (1H, t, J = 6.0 Hz).

2,4-Диамино-N-(3,4-метилендиоксибензил)бензамид (6.47 г) суспендировали в 50 мл этанола и постепенно добавляли 3 мл 47% водной бромистоводородной кислоты. После завершения осаждения кристаллов растворитель полностью отгоняли в вакууме. К остатку добавляли диметилсульфоксид (30 мл), смесь нагревали при перемешивании и 150^oC 1 ч и диметилсульфоксид отгоняли в вакууме. Остаток очищали колоночной хроматографией на силикагеле (растворитель: толуол/этилацетат (1:1)) и получали 1.80 г указанного в заголовке соединения в виде белых кристаллов, выход 22%.Example 143
5-Bromo-2,4-diamino-N- (3,4-methylenedioxybenzyl) benzamide

2,4-Diamino-N- (3,4-methylenedioxybenzyl) benzamide (6.47 g) was suspended in 50 ml of ethanol and 3 ml of 47% aqueous hydrobromic acid was gradually added. After completion of the crystal deposition, the solvent was completely distilled off in vacuo. Dimethyl sulfoxide (30 ml) was added to the residue, the mixture was heated with stirring and 150 ^° C. for 1 hour, and dimethyl sulfoxide was distilled off in vacuo. The residue was purified by silica gel column chromatography (solvent: toluene / ethyl acetate (1: 1)) to obtain 1.80 g of the title compound as white crystals, yield 22%.

Mp 148-150 ^o C.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ:
4.25 (2H, d, J = 5.9 Hz), 5.45 (2H, s), 5.97 (2H, s), 6.02 (1H, s), 6.49 (2H, s), 6.74 (1H, dd, J = 1.6, 8.1 Hz), 6.82 - 6.86 (2H, m), 7.62 (1H, s), 8.44 (1H, t, J = 5.9 Hz).

The study of the claimed compounds for acute toxicity
The compound of Example 43 was administered to rats in a vein. The compound obtained in example 110 was administered to rats orally. In the case of the compound of Example 43, no death of rats was noted upon administration of the compound at a dose of about 20 mg / kg or less. In the case of the compound of Example 110, no death of rats was noted upon administration of the compound at a dose of about 600 mg / kg or less.

Claims (5)

1. Derivatives of anthranilic acid of General formula I or their pharmacologically acceptable salts

where R ¹ , R ² , R ³ and R ⁴ are the same or different and mean a hydrogen atom, a halogen atom, an optionally halogenated lower alkoxy group, a nitro, cyano group, a pyrazolyl group, a group of the formula

where R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom, the lower alkyl group P is an integer from 0 to 6,
group of formula

where R ¹³ represents a hydrogen atom, a lower alkyl group,
q is an integer from 0 to 2;
and R ² may be a 1,2,4-triazolyl group;
R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, or R ⁵ and R ⁶ together with the carbon atoms to which they are attached form an oxolane ring, 1,3-dioxolane or 1,4 a dioxane ring;
W represents a group - N = or —CH =;
R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a lower alkyl group,
or R ¹ and R ⁷ together with the carbon and nitrogen atoms respectively to which they are attached form a piperidine or pyrrolidine ring;
A represents a hydrogen atom, an optionally halogenated lower alkyl group or a group of the formula —X— (CH ₂ ) _m —Z, where X is —CO—, —CH ₂ - or —S (O) ₂ -;
Z represents hydrogen, halogen, a phenyl group which may be substituted by lower alkyl, lower alkoxy, carboxy or lower alkoxycarbonyl groups, a pyridyl group, a group of formula NR ¹¹ R ¹² , where R ¹¹ and R ¹² , together with the nitrogen atom to which they attached, form a piperidine or pyrrolidine ring, which may be substituted by a lower alkyl group, an oxy group, a carboxy group, a lower alkoxycarbonyl group, a cycloalkyl group containing 3 to 8 carbon atoms, which may be substituted by an oxy ppoy, a cyano group, a lower alkylcarbonyloxy group, a carboxy group or a lower alkoxycarbonyl group, a piperidyl group;
m is an integer from 0 to 6;
Y represents an oxygen atom;
n is an integer from 6 to 6. 2. Derivatives of anthranilic acid of General formula II or their pharmacologically acceptable salts

where R ¹ - R ⁴ are the same or different and mean a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, a pyrazolyl group;
R ² may be a 1,2,4-triazolyl group;
R ¹⁴ represents phenylalkyl substituted with a lower alkoxy group;
R ¹⁵ represents an amino group. 3. Derivatives of anthranilic acid of General formula III or their pharmacologically acceptable salts

where R ¹ - R ⁴ have the meanings indicated in claim 2 of the formula;
R ⁸ means a hydrogen atom;
And means a hydrogen atom, a group of the formula -X- (CH ₂ ) _m -Z, where X is CO;
Z represents a group of the formula —NR ¹¹ R ¹² in which R ¹¹ and R ¹² , together with the nitrogen atom to which they are attached, form a piperidine or pyrrolidine ring, optionally substituted with an oxy group, a carboxy group or a lower alkoxycarbonyl group;
m is an integer from 0 to 6. 4. Derivatives of anthranilic acid of General formula IV or their pharmacologically acceptable salts

where R ¹ - R ⁴ represent a hydrogen atom, a halogen atom;
m is an integer from 0 to 6;
Z represents a phenyl group substituted with a lower alkoxycarbonyl group.  5. A drug exhibiting inhibitory activity against cyclic guanosine monophosphate phosphodiesterase, characterized in that it contains an effective amount of an anthranilic acid derivative or its pharmacologically acceptable salt according to claim 1 and a pharmacologically acceptable carrier. 6 Priority by signs:
12/27/93 - R ¹ , R ² , R ³ or R ⁴ are the same or different and represent a hydrogen atom, a halogen atom, an optionally halogenated lower alkoxy group, a nitro group, a cyano group, a group of the formula - (CH ₂ ) _p -NR ⁹ R ¹⁰ , a triazolyl group, a pyrazolyl group, a group of the formula -S- (O) _q -R ¹³ (where R ¹³ represents a hydrogen atom or a lower alkyl group and q is an integer from 0 to 2);
R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a lower alkyl group,
W represents a group of the formula —CH═;
A represents a hydrogen atom, an optionally halogenated lower alkyl group or a group of the formula —X— (CH ₂ ) _m —Z wherein X is —CO— or —CH ₂ -;
11/09/94 - R ¹ , R ² , R ³ or R ⁴ are the same or different and represent a hydrogen atom, a halogen atom, an optionally halogenated lower alkoxy group, a nitro group, a cyano group, a group of the formula - (CH ₂ ) _p -NR ⁹ R ¹⁰ , a triazolyl group, a pyrazolyl group, a group of the formula -S- (O) _q -R ¹³ (where R ¹³ represents a hydrogen atom or a lower alkyl group and q is an integer from 0 to 2);
R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a lower alkyl group, or R ¹ and R ⁷ together with the carbon and nitrogen atoms to which they are respectively attached form a ring;
W represents a group of the formula —N═ or —CH═;
A represents a hydrogen atom, an optionally halogenated lower alkyl group or a group of the formula —X— (CH ₂ ) _m —Z, where X is —CO—, —CH ₂ - or —S (O) ₂ -

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